The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule.
KEYWORDS: NKT cells, adaptive immune response, adaptive immunity, bacterial agents, fungal agents, glycolipids, innate immune response, innate immunity, pathogens, viral agents
SUMMARY
The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.
INTRODUCTION
The immune system is a complex array of molecules, cells, tissues, and organs synchronized to respond virtually to any molecule, both self or foreign (1). The components of the immune system are traditionally divided into two subsets: innate and adaptive (1, 2). The innate immune response is commonly characterized as fast and non-antigen oriented and is responsible of an early and swift reaction (1). The adaptive immune response is an antigen-oriented reaction. An initial antigen exposure will result in a slow response, while subsequent exposures will cause a fast and well-modulated memory reaction (1–3). Both responses are fine-tuned by the effect of cytokines and chemokines (1–3).
The cells of the innate immune system include myeloid-derived cells, such as polymorphonuclear cells (PMNs) (neutrophils, eosinophils, and basophils), monocytes, and macrophages (1), lymphoid-derived cells, such as innate lymphoid cells (ILCs), which are divided into ILC1s, ILC2s, ILC3s, LTis, and cytotoxic ILCs (commonly known as natural killer [NK] cells) (4), innate-like T cells, which include γδ T cells, natural killer T (NKT) cells, and mucosa-associated invariant T (MAIT) cells (5), and cells of mixed ontogeny, such as dendritic cells (DCs). Among these innate cells, macrophages and DCs are considered professional antigen-presenting cells (APCs), as they are capable of performing phagocytosis and presenting antigens on major histocompatibility complex (MHC) molecules, either class I or II. Remarkably, class II MHC is only expressed by professional APCs (1).
Cells of the adaptive immune response include T and B lymphocytes, which can be activated by different stimuli, such as antigen presentation by APCs or cytokine stimulation (1). The genetic segments responsible for antigen recognition of the T cell receptor (TCR) and the B cell receptor (BCR) show high sequence diversity, generating an enormous variability of their affinity and ability to recognize different antigenic structures, allowing T and B cells to respond to virtually any antigen (1).
NKT cells, the focus of this review, were first described in 1995 (6–8). They share characteristics of both NK cells and T lymphocytes (Fig. 1) (9, 10). Even though both NK and T cells are derived from a lymphoid lineage, NK cells are considered innate-responsive cells, whereas T cells are considered an adaptive-responsive cell type (1). As stated above, NKT cells are considered innate-like T cells (5), being capable of generating responses against a wide range of specific molecules, and acting as a bridge, linking the innate and the adaptive immune responses (11), as will be discussed next.
FIG 1.
Type I natural killer T cell characteristics. iNKT cells are innate-like T cells, with characteristics of both innate and adaptive immune cells. The mixed expression of surface markers, such as NK1.1 and Ly49 from NK cells and an invariant TCR from T cells, allows them to surpass the borders commonly defined between the innate and the adaptive responses. iNKT cells also express several cytokine receptors (such as IL-12R), modulatory molecules (such as PD-1 and CD40L), and cytotoxic molecules (such as granzymes and perforins), giving them a plethora of possible responses for each different context.
NKT cells can also be divided into two subsets. Type I NKT cells, or invariant NKT (iNKT) cells, are described as nonconventional T cells that express an invariant TCR, meaning that this receptor does not derive from a highly diverse genetic recombination process, as occurs for conventional T cells. In addition, iNKT cells express several NK receptors, such as NK1.1 and Ly49-related receptors (Fig. 1) (9, 10, 12). The TCR on iNKT cells is restricted to the interaction with an MHC-I-like molecule known as CD1d, which is differentially expressed by various species. Type II NKT cells express a more diversified repertoire of TCR molecules (their TCRα chain is not restricted), although they still interact with CD1d in a more flexible manner (13). Since type I NKT cells are the focus of this review, to learn more details about type II NKT cells, please refer to previously published articles (14–16).
The CD1 molecule can be found on the surfaces of both hematopoietic and nonhematopoietic cells, is more abundantly expressed by APCs, and is loaded with antigens of lipid nature, inducing the activation of several immune cells (9). The CD1 gene family in humans comprises five members (CD1A, CD1B, CD1C, CD1D, and CD1E), whereas mice only harbor the CD1D gene (with two loci, mCD1D1 and mCD1D2). CD1d has been widely characterized along with its capacity to interact with the TCR of NKT cells (17).
A variety of molecules with the capacity to bind to CD1d have been described, and various analogs of these molecules have been synthetized. When bound to CD1d, these molecules can activate iNKT cells. The activation of iNKT cells induces the secretion of cytokines and the polarization and activation of several immune cells (18), as will further be discussed (Fig. 2, 3, and 4). One of the better-characterized molecules that binds to CD1d is α-galactosylceramide (αGalCer; commonly named KRN7000), a synthetic glycolipid derived from a molecule initially isolated from Agelas mauritianus, a marine sponge (19). However, several lipid antigens have been described to bind to CD1d (10), as will further be discussed.
FIG 2.
Interaction of iNKT cells with the innate repertoire. The versatility of iNKT cells will also play a role in the interaction with cells of the innate immune response. These interactions will result in a promptly enhanced early response, with different effects depending on the cell type that is targeting. In this line, iNKT cells may secrete several cytokines that will play a role in this response. The interactions of iNKT cells with dendritic cells, epithelial cells, macrophages, mast cells, natural killer cells, and neutrophils are depicted in this figure. Accordingly, stimuli are indicated in blue font, while responses are indicated in red font.
FIG 3.
T lymphocyte polarization induced by iNKT cells. Dendritic cell-iNKT cell interaction (through the CD1d and TCR molecules expressed by the respective cells) can induce the polarization of CD4+ T cells into specific responsive profiles. This DC-iNKT cell interaction can also induce the polarization of other iNKT cells into the different effector profiles discussed in the text. This polarization will be modulated by several factors such as the nature of the antigen-CD1d complex expressed by DCs and will have different results depending on the transcription factor induced and the hallmark cytokines secreted. TH1, TH2, and TH17 T cell polarizations are depicted, which also have their respective responses in iNKT cells (dashed arrows).
FIG 4.
Follicular and extrafollicular B lymphocyte-iNKT cell interaction. To maturate and differentiate into effector plasma cells, typically, B cells must be stimulated by T cells via interaction of their CD40 and CD40L surface receptors. However, iNKT cells have also been described to play a role in this interaction. Particularly, extrafollicular iNKT cells are capable of interacting with antigens presented in the CD1d molecule of B cells, prompting an early secretion of low-affinity antibodies by early-differentiated plasma cells. Follicular NKT cells will also promote the differentiation of B cells into plasma cells, stimulating the hypermutation and affinity maturation processes via IL-4 secretion. This will result in the secretion of high-affinity antibodies by these mature plasma cells.
iNKT cells in mice and humans share many features but differ in several others. For instance, the TCRα chain expressed by human iNKT cells consists of the Vα24-Jα18 recombination, while mice express the orthologous Vα14-Jα18 recombination (12, 20). Accordingly, the TCRβ chain expressed by human iNKT cells is restricted mostly to Vβ11, while mice can express either Vβ8, Vβ7, or Vβ2 (12, 20). Notably, the α chain of the TCR contributes majorly to the molecular interaction with the CD1d:antigen complex, while the β chain interacts only with the CD1d molecule (21). Among the most used models for the study of NKT cells are the Jα18KO mice, which lack iNKT cells due to their inability to express the invariant TCRα chain (22), and the CD1d knockout (KO) mouse, which fails to develop NKT cells—either type I or type II—due to a CD1d deficiency (11).
The frequency of iNKT cells differs among different organs and also between humans and mice, as reported in the literature. While in humans, iNKT cells represent approximately 0.05% and 1% of the total lymphocytes found in the liver, in mice, the frequency of these cells is approximately 12% to 30% of total lymphocytes (23, 24). While the frequency of circulating iNKT cells in humans is close to 0.01% to 0.1%, in mice, the frequency is close to 0.2% of total lymphocytes (23). In mice, the presence of iNKT cells has been described in several other organs. Particularly, their frequency in the lungs is approximately 5% to 10% of total immune cells. Lower frequencies have been described for other organs, such as bone marrow, with 0.4% to 8%, the spleen, with 1% to 3%, the thymus, with 0.5% to 1%, the lymph nodes, with 0.2% to 1%, and the intestine, with 0.05% to 0.6% (23–26).
In addition to the variant distribution of these cells between mice, humans, and the respective organs, differences are also observed among different stimuli, modulating the frequency of iNKT cells (27–30). For example, it has been shown that acute infection of mice with lymphocytic choriomeningitis virus (LCMV) induces selective apoptosis of iNKT cells in the liver (by activation-induced cell death) as soon as 2 to 3 days postinfection (p.i.). The recovery of these cells required up to 3 months in order to be fully achieved, as reported in these studies (27, 28). Treatment with poly(I·C) induced the same loss of iNKT cells described for LCMV, and this reduction was not dependent on the production of gamma interferon (IFN-γ) or interleukin 12 (IL-12), cytokines commonly secreted during viral infections (27). It was suggested that activation-induced cell death was independent of CD28 and Fas stimulation, which could be associated with the induction of type I IFN, and that was not explained by TCR internalization or loss of surface markers, such as NK1.1 (27, 28).
iNKT cells can respond faster than conventional T cells and more diversely upon TCR stimulation (or even upon stimulation with specific cytokines), rendering them able to surpass the borders commonly defined between innate or adaptive responding cells. This point will be further discussed in the following sections.
CONTRIBUTION OF iNKT CELLS TO THE IMMUNE RESPONSE
iNKT Cells and Their Role in the Innate Response
Since iNKT cells can secrete cytokines faster than conventional T cells upon TCR engagement, they play a major role at modulating early stages of the innate immune response, such as inflammation, infiltration of different cells types, and the secretion of cytokines by other immune cells. Moreover, NKT cells can be indirectly activated by cytokines available in their vicinity (31). In the following section, the consequences of the stimulation with αGalCer and the resulting modulation of the innate immune response will be described, as this molecule represents the best-characterized ligand inducing iNKT cell activation (Fig. 2). However, stimulation with αGalCer is considered an artificial therapeutic approach rather than the physiological endogenous mechanism for in vivo stimulation of iNKT cells.
Upon administration, αGalCer is taken by APCs, such as DCs or macrophages, and presented on CD1d to iNKT cells (32). This process leads to a quick activation of iNKT cells in a matter of a few hours (contrary to what is required by conventional T cells), inducing the secretion of several cytokines (32). An early secretion of IL-4 and a late secretion of IFN-γ (modulating inflammation, in this way) along with the expression of different activation markers also detected in conventional T cells, such as CD25 and CD69, are observed (33). Remarkably, iNKT cell activation seems to induce a transient internalization of the TCR and downregulation of NK1.1, which makes it difficult to detect this population at early time points after activation (34). Treatment with αGalCer induces internalization of the TCR starting at 1 h poststimulation, reaching a peak at 8 to 12 h poststimulation, and returning to basal levels 24 to 48 h after the stimulation. Interestingly, this behavior was detected both in vivo and in vitro in the mouse model (34). Expression of the programmed death-1 (PD-1) receptor is increased on the surfaces of iNKT cells, which can bind to PD-L1 and PD-L2 (molecules expressed on the surfaces of APCs and other immune cells), inducing an anergic state in NKT cells (34, 35). Along with the secretion of cytokines and the changes in surface marker expression, iNKT cells also rapidly proliferate, reaching a peak at day 3 or 4 poststimulation (Fig. 2) (36).
Two of the most significant elements of the modulation of the innate response by iNKT cells are the transactivation of NK cells and the modulation of the cytokine secretion pattern of DCs. Historically, cross talk between iNKT cells, NK cells, and DCs was one of the first topics to be studied, and the mechanisms underlying these interactions will be discussed in the following paragraphs (Fig. 2).
Upon stimulation with αGalCer, iNKT cells induce intense and swift activation and proliferation of NK cells (37, 38). Transactivation (defined as a nondirected activation) of NK cells by iNKT cells is an IFN-γ-dependent process that is also enhanced by IL-12 produced by DCs (38). NK cell activation provides an additional boost in IFN-γ secretion, enhancing their cytotoxic functions, which is crucial for the clearance of viral infections and the killing of tumor cells. It is important to note that both NK and iNKT cells express the IL-12 receptor (IL-12R) on their surfaces, rendering them responsive to this cytokine (39). Among the major IL-12 producers are DCs, and iNKT cells have been shown to promote the secretion of IL-12 by DCs. Secretion of IL-12 is induced in a CD40/CD40L-dependent manner, implying a necessary physical interaction between DCs and iNKT cells (32). The establishment of such an interaction triggers increased expression of the IL-12R by iNKT cells, thereby promoting a positive feedback loop between iNKT cells and DCs: once stimulated with IL-12, NKT cells secrete IFN-γ, which in turn stimulates DCs to secrete more IL-12 (32). This type of positive feedback is also observed between NK cells and DCs during localized bacterial infections, leading to massive tissue damage (Fig. 2) (39).
Since iNKT cells are a source of IFN-γ, they can enhance phagocytosis by macrophages, as also described for NK cells and T cells (40). Additionally, IFN-γ-secreting iNKT cells can secrete CCL3 (MIP-1α) when exposed to immune complexes in an FcγR-dependent manner. CCL3 secretion induces higher IL-1β and TNF-α production by alveolar macrophages and DCs (41). The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by iNKT cells can also enhance IL-1β secretion by peritoneal macrophages. NKT cells also play an anti-inflammatory role by secreting large amounts of IL-4 and therefore promoting differentiation of macrophages into a regulatory M2 profile, leading to a decrease in IL-1β secretion (Fig. 2) (42).
iNKT cells also modulate neutrophil-mediated responses. For instance, IFN-γ-producing iNKT cells can secrete IL-10, which inhibits CD55 expression (the complement decay-accelerating factor) in neutrophils. Such inhibition leads to an enhanced formation of the C3 convertase complex and a subsequent increase in the activity of the molecules associated with the complement system, including the C5a anaphylatoxin (43). Tumor necrosis factor alpha (TNF-α)-secreting iNKT cells are capable of inducing the secretion of the neutrophil-attractant chemokines CXCL1, CXCL2, and CXCL3 by epithelial cells. This secretion will lead to greater neutrophil infiltration, reactive oxygen species (ROS) generation, and even more TNF-α secretion (44). iNKT cells can also downregulate chronic neutrophil migration to wound sites through early and controlled IL-17 production (Fig. 2) (45).
Lastly, iNKT cells can interact with mast cells and, therefore, play a role in histamine secretion. Mast cells express CD1d shortly after degranulation, and iNKT cells can interact with this cognate ligand through their invariant TCR, as indicated above. Interaction with mast cells induces the proliferation of iNKT cells and the secretion of IFN-γ, IL-4, and IL-13 (46), suggesting that NKT cells may play a role during allergic responses. Additionally, mice lacking the gene encoding histamine exhibit reduced numbers of iNKT cells, and histamine enhances IFN-γ and IL-4 production by iNKT cells (47), further supporting this notion (Fig. 2).
Most changes indicated above are accompanied by the interaction of iNKT cells with other innate immune cells (Fig. 2). Among these innate-immunity-related interactions are, particularly important, the activation of DCs and macrophages in response to IL-12 and the CD40-CD40L engagement (32) and the transactivation of NK cells (38) and their capability to hastily secrete cytokines, allowing them to induce the recruitment and modulation of various myeloid cells (48). Furthermore, iNKT cells can recruit neutrophils, which will also secrete IFN-γ, exacerbating the early inflammatory response (49).
Modulation of the Adaptive Immune Response by iNKT Cells
The adaptive immune response elicited upon exposure to different antigens (and, therefore, the loss of homeostasis) has been categorized by the scientific community according to the type of cytokines that CD4+ T cells secrete. This categorization is roughly based on the pattern of cytokines produce by CD4+ T cells once they are activated and differentiate into either TH1, TH2, or TH17 profiles (1). The capability of these cytokines, and the respective induced profile, to resolve pathogenic infections and restore the homeostasis has been widely studied (Fig. 3) (1). For a more profound knowledge of the adaptive immune response and its relationship with iNKT cells, the characteristics of T cell polarization profiles will be discussed below along with iNKT cell polarization profiles.
For conventional T cells, TH1 polarization requires stimulation with IL-12 and is associated with an increased expression of T-bet, which is a transcription factor that promotes this differentiation and the secretion of hallmark inflammatory cytokines, such as IFN-γ. This profile exhibits enhanced capacities for the clearance of intracellular pathogens and the killing of tumor cells (50). TH2 polarization requires priming with IL-10 and increased expression of the transcription factor GATA-3 and is characterized by the production of IL-4 and IL-5, both anti-inflammatory cytokines. This profile represents a top-of-the-line response for the clearance of extracellular pathogens (50). TH17 polarization is induced by stimulation with IL-6 and transforming growth factor β (TGF-β) and comprises increased expression of the transcription factor RORγt. This profile is characterized by the secretion of IL-17 and is commonly induced upon exposure to extracellular pathogens in the skin or mucosal tissues. Secretion of any of these cytokines enhances the polarization toward one profile and, concomitantly, inhibits the others (Fig. 3) (50). iNKT cells may also play a role in the activation of T cells, promoting their polarization toward their respective activated lineages (51).
Polarization toward distinctive profiles (with their cytokine hallmarks) has also been described for iNKT cells. Due to their resemblance to T cells, the polarization profiles of these cells are in line with the pattern of cytokines they secrete. Therefore, NKT1 (mainly secretes IFN-γ), NKT2 (mainly secretes IL-4), and NKT17 (mainly secretes IL-17) (48, 52) profiles have been described. Despite their commitment toward these profiles, they also can produce other cytokines upon polarization (such as IL-4 for NKT1). Other profiles have also been suggested as candidates, such as NKT10 and follicular helper NKT (NKTFH) (Fig. 4) (10). Since NKT cells are closely related to both NK cells and T cells, they also secrete perforins and granzymes. These two molecules are known to induce cell death in target cells, giving iNKT cells even more control over the modulation of the early innate response (53).
It is not just T lymphocytes that can interact with iNKT cells, as interactions with B lymphocytes have also been reported (54–59). iNKT cells may play a significant role in the activation and maturation of B cells, modulating the early secretion of antibodies by extrafollicular plasma cells and the late secretion of more specific antibodies by follicular plasma cells (Fig. 4) (54–59). Canonically, to induce the secretion of antibodies, B cells must be stimulated by T cells via interaction of their CD40 and CD40L (CD154) molecules, respectively (among various other T cell-derived stimuli) (1, 54). The T cell-B cell interaction can occur in the follicular or the extrafollicular zone of secondary lymphoid organs (1, 54). Extrafollicular space interactions lead to a repertoire of plasma cells secreting antibodies with lower affinity against the target antigen than T cell-B cell interactions occurring at the follicular zone. Extrafollicular iNKT cells can interact with antigens presented by the CD1d molecule of B cells, a process that can contribute to their differentiation into plasma cells. This B cell differentiation process is T cell independent and mainly dependent on the stimulation with CD40-CD40L, B7-1/2 (CD80/CD86), and the production of IFN-γ (Fig. 4) (55, 59). B lymphocytes that become activated in the germinal centers (found in the follicular zones of secondary lymphoid organs) also undergo T cell-induced somatic hypermutation and affinity maturation, mechanisms that will increase the affinity of their antibodies and enhance the capacity of these antibodies to recognize the target antigen (55). iNKT cells are also able to induce the activation of B cells in germinal centers (54). This follicular B cell activation requires waves of IL-4 derived from NKTFH, which will induce the germinal reaction and the subsequent differentiation of B cells into affinity-matured and somatically hypermutated plasma cells (Fig. 4) (54, 60).
iNKT cells become activated upon engagement of their TCR with the cognate glycolipid:CD1d complex. αGalCer is a widely described lipid capable of inducing proliferation and differentiation of iNKT cells into a mixed TH1/TH2 subset (32, 61). Upon stimulation, a characteristic early secretion of IL-12 and a later secretion of IFN-γ and IL-4 are reported (32, 61). The molecule KRN7000 [chemical name (2S,3S,4R)-1-O-(α-d-galactopyranosyl)-N-hexacosanoyl-2-amino-1,3,4-octadecanetriol] is the name given to artificially synthetized αGalCer, and several analogs of this molecule have also been synthetically generated, exhibiting different capacities to induce activation and differentiation of iNKT cells into one of the previously described profiles (62, 63). The molecule termed 7DW8-5 [chemical name (2S,3S,4R)-1-O-(α-d-galactopyranosyl)-N-[11-(4-fluorophenyl)undecanoyl-2-amino-1,3,4-octadecanetriol]) is an αGalCer analog, capable of inducing an even more potent NKT1 response than αGalCer (as seen for in vivo studies) working as an adjuvant, prompting a significant increase in the secretion of IFN-γ (62, 64). 7DW8-5 was first synthesized in 2010 along with a library of 24 other analogs confirmed to engage and activate iNKT cells, with a significant association between their structure and activity. αGalCer analogs with fatty acyl chains longer than 15 carbon atoms induced a significant decrease in the secretion of IFN-γ. Also, the addition of one fatty acyl terminal benzene ring enhanced the polarization toward an IFN-γ-secreting NKT1 profile (62). The molecule named OCH [chemical name (2S,3S,4R)-1-O-(α-d-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol] is a synthetic compound with only nine carbon atoms in the acyl chain; it induced a strong NKT2 cell response, with a predominant secretion of IL-4 upon stimulation (65). This ligand was shown to be particularly efficient for the treatment of experimental autoimmune encephalomyelitis (EAE), because it induced the secretion of IL-4, while the secretion of IFN-γ was reduced to a minimum. Since IL-4 is thought to play a protective role in autoimmune diseases (such as multiple sclerosis and EAE), the OCH ligand may be used in future clinical trials (65). Additional unsaturation of the acyl chain of KRN7000 was used to generate the analog C20:2, a potent inductor of the NKT2 profile. The C20:2 compound promoted increased secretion of IL-4 and a marked decrease of IFN-γ secretion, as reported for OCH (61, 66). The use of these analogs capable of inducing the secretion of certain anti-inflammatory cytokines may potentially be useful for the treatment of autoimmune and inflammatory diseases (63).
Naturally synthesized αGalCer-like molecules have been discovered in several microorganisms. For instance, Bacteroides fragilis, a commensal gut bacterium, contains in its membrane an activating αGalCer-like molecule (αGalCerBf) with similar properties to those described for KRN7000 (67). Bf717 is an αGalCer-like molecule with inhibitory activity, and it was also described in B. fragilis (68). Bf717 was shown to inhibit iNKT cells expansion, suggesting that B. fragilis may have coevolved to modulate the response elicited by iNKT cells in the host. The list of molecules has become extensive, as the synthesis and the discovery of different αGalCer analogs is still a current topic, with either enhanced or decreased induction into one or another iNKT profile depending on the molecule reported (Table 1).
TABLE 1.
Summary of roles described for NKT cells in infectious diseases
| Type of disease | Pathogen | General effect | Observed NKT cell-driven effector functions during infection (reference[s]) | NKT cell-derived cytokines (reference[s]) | Relevant antigen(s) for NKT cell activation | Mechanism of NKT cell activation (reference[s]) | Effector functions upon exogenous stimulation (reference[s]) |
|---|---|---|---|---|---|---|---|
| Pulmonary diseases | Pseudomonas aeruginosa | Protective, controversial | No changes in neutrophil infiltration (159); increased neutrophil infiltration (158); increased phagocytic capacity of alveolar macrophages (158) | IFN-γ secretion (157–159) | αGalCer augments IFN-γ secretion (159) | ||
| Streptococcus pneumoniae | Protective | Increased frequency of NKT cells (73); activation of regulatory T cells (74) | IFN-γ and IL-17 secretion (75) | Gal-Glc-DAG, Glc-DAG | Loaded onto CD1d and subsequent TCR-driven NKT cell activation (75) | αGalCer enhances the clearance of the infection (74) | |
| Mycobacterium tuberculosis | No role preventing the infection; protective in disease resolution; uncertain during granuloma formation | Enhanced activation of B cells (83); enhanced survival upon challenge with lethal dose (83); induction of granuloma formation (87); killing of infected macrophages (88) | IFN-γ and GM-CSF secretion (80, 82) | PIM4 | Loaded onto CD1d and subsequent TCR-driven NKT cell activation (84) | αGalCer enhances the activation of NKT cells, aiding in the clearance of M. tuberculosis (86) | |
| Influenza A virus | Protective | Inhibition of the expansion of myeloid-derived suppressor cells (91); induction of an antiviral B cell response (60); control of exacerbated inflammation (92); enhancement of the effectiveness of immunization (93–95) | Reduced viral loads (90); less marked body weight loss (90) | ||||
| Severe acute respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2 | Uncertain | NKT cells are more abundant in the lungs of infected mice by 7 days postinfection (163); circulating NKT cells in peripheral blood were higher than in healthy controls, peaking at 7 days after the onset of symptoms (164) | |||||
| Human respiratory syncytial virus | Protective, controversial | Promotion of early innate response (90); enhanced proliferation of CD8+ T cells (169); increased eosinophil infiltration (170); no differences in wt loss, cells infiltrating to the lungs, histopathological scores, and viral loads were seen among infected CD1d−/− mice compared to that in mock-treated mice (171) | IFN-γ secretion (169) | Reduced viral loads (169); induction of asthma-like symptoms (170); significant decrease in the secretion of IL-2 in cocultures with hRSV-infected DCs (171) | |||
| Human metapneumovirus | Uncertain | NKT cells do not play a significant role during hMPV infection, as their presence or absence has no impact on the parameters measured (171) | Significant decrease in the secretion of IL-2 in cocultures with hRSV-infected DCs (171) | ||||
| Cryptococcus neoformans | Protective | Promotion of a TH1 profile adaptive response (100) | Early secretion of IFN-γ (98, 100) | αGalCer induces lower fungal burden (98) and increased DTH (101) | |||
| Aspergillus fumigatus | Controversial, exacerbation | Induction of airway hyper-reactiveness (178); delayed fungal clearance when membrane glycosphingolipids are presented (178); Inhibition of exacerbated pulmonary inflammation (175); faster fungal clearance when cell wall β-glucans are presented (175) | IFN-γ secretion (175) | Asperamide B | Loaded onto CD1d and subsequent TCR-driven NKT cell activation (178) | αGalCer induces lower fungal burden (175) | |
| β-1,3 glucans (zymosan, scleroglucan, curdlan) | Recognized by dectin-1 on DCs, which activate NKT cells through IL-12 in a TCR-independent fashion (175) | ||||||
| Gastrointestinal diseases | Salmonella spp. | Protective | NKT cells are activated within the first 24 h (112); promotion of a TH1 profile adaptive response (112) | IFN-γ secretion (112) | LPS | DCs which activate NKT cells recognize it (113) | |
| Listeria monocytogenes | Protective, controversial | Activation of macrophages (129) | IFN-γ, TNF, and IL-12 secretion (120) | Administration of an anti-CD1 antibody increases cytokine secretion (120); αGalCer induces IFN-γ secretion (129) | |||
| Hepatic diseases | Hepatitis B virus | Protective, damage | Inhibition of HBV replication through IFN (133); decreased circulating NKT cell frequency in chronic hepatitis B patients (132); higher no. of circulating IFN-γ+ NKT cells correlates with lower HBV viral load (138); IL-4+ NKT cells promote hepatic damage (138) | Type I, II, and III IFN | Modulation of CD28 and PD-1 expression | ||
| Hepatitis C virus | Controversial, uncertain | Similar circulating NKT cell frequency between HCV patients and healthy controls (140); lower frequencies of circulating NKT cells in HCV patients than in healthy controls (141) | |||||
| Dengue virus | Protective, uncertain | NKT cells recruit mast cells to achieve DV clearance (144); NKT cell depletion decreased severity of dengue illness (145) | |||||
| Blood and systemic diseases | Borrelia burgdorferi | Protective | Recognition of two glycolipids independent of APCs (153); promotion of a TH1 profile adaptive response (149) | Secretion of IFN-γ (149) | BbGl-1, BbGl-2 | Both of them are recognized by the TCR from the NKT cells, activating these cells (150, 151) | |
| Human immunodeficiency virus | Uncertain | Quantities of Vα24+ CD161+ NKT cells were inversely related to viral loads (192, 193) | Lower secretion of IFN-γ and IL-4 upon stimulation with αGalCer (193) | ||||
| Leishmania donovani | Exacerbation (human), protective (mice) | Lower parasitic burden in mice (196, 197); promotion of granuloma maturation in mice (196, 197); accumulation of IL-10-secreting CD4+ NKT cells in humans (198, 199); apoptosis of CD8+ NKT cells in humans (199) | Higher TNF-α secretion in mice (197) | LPG, GIPL | Loaded onto CD1d and subsequent TCR-driven NKT cell activation (196) | ||
| Leishmania major | Controversial, dependent on mouse model used | Lower parasitic burden in BALB/c mice (201, 203); induction of smaller cutaneous lesions in BALB/c mice (203); higher parasitic burden in C57BL/6 mice (203); induction of larger cutaneous lesions in C57BL/6 mice (203); enhancement of cDC1 activity (202). | PBS57, an αGalCer analog, enhances lesion vol (203) | ||||
| Plasmodium spp. | Controversial, uncertain | Inhibition of hepatocyte infection by sporozoites; no role during erythrocytic infection (206); lower levels of parasite RNA in vivo (206); lower parasitic burden in vitro (207); no differences in blood parasitemia in vivo (207); boosting of humoral response (210) | Early IFN-γ secretion (206) | Prophylactic αGalCer administration inhibits sporozoite infection (206); αGalCer analogs boost IFN-γ secretion (206, 208, 209) | |||
| Kidney-related diseases | Chlamydia muridarum | Exacerbation | Enhanced wt loss (181); higher bacterial burden (181) | IL-4 secretion (181) | αGalCer induces higher secretion of IL-4 | ||
| Candida albicans | Exacerbation | No change in wt loss, fungal burden, or cytokine secretion (183); higher fungal burden (184); lower survival rates (184); more susceptible to infection (185) | No changes in cytokine secretion (183); increased IFN-γ and IL-6 secretion (184); increased IL-10 secretion (185) | ChAcMan, ChAcGlc, ChAcGal | Loaded onto CD1d and subsequent TCR-driven NKT cell activation | αGalCer induces IFN-γ secretion, and lower counts of bone marrow and circulating neutrophils (184) |
It has been shown that a secondary stimulation with αGalCer induces hyporesponsiveness in iNKT cells, described as a significantly weaker response than the initial stimulation, with reduced proliferation and secretion of cytokines (69). This response suggests that restimulation with αGalCer may not be a suitable approach for clinical therapies, in light of the hyporesponsive profile described upon following stimulations.
PROTECTIVE ROLE OF iNKT CELLS DURING INFECTIOUS DISEASES
Probably the most crucial task that needs to be accomplished by the immune system is to tolerate and control self-originated danger signals while attacking external threats, such as pathogenic viruses and bacteria. Indeed, there is a thin line separating the protection and the harm caused by the immune response during an infection. In this section, the focus will be the protective role reported for iNKT cells against a wide range of infectious agents causing pathologies, such as pulmonary, gastrointestinal, liver, and blood infections among others (Table 1 and Fig. 5A) (48, 70).
FIG 5.
Role of iNKT cells in the pathogenesis of several diseases. (A)The protective role of iNKT cells during infectious diseases is depicted, with an emphasis on the organs where the diseases develop. (B) Accordingly, the negative or controversial role of these cells is depicted, with the same emphasis. For further details on these effects and the literature associated with them, please refer to Table 1.
As indicated above, the two most widely used models for the study of iNKT cells are the Jα18−/− and the CD1d−/− mice, which lack genes encoding either the joining region of the TCRα chain of iNKT cells or the MHC-like antigen-presenting molecule (CD1d), respectively. Many studies have used Traj18−/− mice as a Jα18 knockout model. Nevertheless, a 2012 report showed that Traj18−/− mice have a limited T cell repertoire, with TCR rearrangements of the α chain lacking up to 60% of diversity, corresponding to those regions upstream of the Traj18 (Jα18) gene, an effect that was independent of the presence or absence of CD1d (71). The Traj18−/− model was widely used previous to the date of publication of this finding and has continued to be used in many studies since. Therefore, caution is suggested for the interpretation of data derived from the Traj18−/− mouse model. This should also be considered when referring to results regarding the adaptive immune response derived from the studies to be described here, particularly in those experiments in which T cell function was analyzed.
iNKT Cells against Infectious Agents Causing Pulmonary Disease
Streptococcus pneumoniae.
Streptococcus pneumoniae is the leading bacterial pathogen causing pneumonia, meningitis, and septicemia, among other diseases, turning this microorganism into a major worldwide health burden (72). How NKT cells respond during an S. pneumoniae infection has been studied extensively. Earlier reports indicated that iNKT cell numbers increased in mice when facing an S. pneumoniae infection, and these cells were required to control the infection (73). Follow-up studies showed that IFN-γ produced from Vα14+ NKT cells was essential for the protective response mediated by neutrophils, and stimulation of Vα14+ NKT through αGalCer contributed to the clearance of the infection, an effect that was inhibited upon administration of an anti-IFN-γ antibody (74).
Later on, it was found that Vα14+ NKT cells were able to secrete IFN-γ and IL-17 in the lungs during an S. pneumoniae infection. Production of these cytokines was dependent on TCR engagement. Recognition of the antigen by the TCR of Vα14+ NKT was essential to achieve the clearance of this pathogen (75). Two glycolipids from S. pneumoniae that can be recognized by the TCRs on iNKT cells from mouse and human have been reported. The first one is a glucose-linked diacylglycerol (named Glc-DAG) and the other one is composed of a galactose molecule additionally linked to Glc-DAG (Gal-Glc-DAG) (Table 1). Treatment of mice with Glc-DAG stimulated Vα14+ iNKT cells and led to an increased expression of IFN-γ by these cells. Treatment with Gal-Glc-DA also stimulated Vα14+ iNKT cells, albeit not as strongly as Glc-DAG, which correlated with reduced induction of IFN-γ (75). The specificity of this response was shown to be conserved in humans as well.
It has been shown that infection with S. pneumoniae is only partially achieved by day 3 p.i. when αGalCer is administered along with the bacterium. However, when αGalCer was administered before a lethal S. pneumoniae infection, a protective response against this pathogen was reported (73, 76). Even though the action of iNKT cells is helpful against S. pneumoniae, the use of specific components derived from S. pneumoniae (such as type 3 polysaccharide, cell walls, pneumolysoid, and CpG oligodinucleotides) can induce the activation of regulatory T cells, leading to the blockage of iNKT cell activity, and therefore contribute to suppressing asthma-like diseases (74, 77).
Based on the information stated above, it seems that iNKT cells are necessary to control S. pneumoniae infection, and that S. pneumoniae-derived glycolipids promote the secretion of IFN-γ. Moreover, blocking the activity of these cells (using other S. pneumoniae structural components) was shown to also suppress allergic diseases affecting the airways (Table 1 and Fig. 5A).
Mycobacterium tuberculosis.
Mycobacteria cause tuberculosis (TB) among other diseases, and the principal representative agent of this genus is Mycobacterium tuberculosis (78). Studies in mice have shown that the lack of iNKT cells does not have a significant effect on the susceptibility against mycobacterial infections (70, 79). In contrast, these cells have been shown to be crucial for the resolution of the disease in humans. iNKT cells from activated TB patients secrete large amounts of IFN-γ, which is especially suited for the clearance of intracellular bacteria, such as M. tuberculosis (80, 81). The activation of iNKT cells through CD1d can also induce the production of GM-CSF (a soluble factor with antibacterial properties) during M. tuberculosis infection. The secretion of GM-CSF by iNKT cells also contributes to inhibiting the growth of M. tuberculosis even in the absence of IFN-γ, because GM-CSF by itself is capable of controlling this bacterial infection (82).
iNKT cells have been reported to exhibit a profile that enhances the activation and proliferation of B cells in patients with TB, promoting their maturation into plasma cells (83). Mature plasma cells are producers of IgG and IgA antibodies, enhancing the adaptive response against this pathogen (83). CD1d can recognize and bind lipids from Mycobacterium bovis bacillus Calmette-Guérin (BCG). Among these lipids, PIM4 is the only one reported so far to bind to CD1d (Table 1). PIM4 activates iNKT cells from mice and humans, while lipoarabinomannan (LAM) and trehalose dimycolate cannot be recognized by CD1d in humans (Table 1) (84). Administration of αGalCer as a therapeutic approach enhanced the activation of iNKT cells and protected mice from a lethal dose of M. tuberculosis. Furthermore, administration of αGalCer to infected mice decreased bacterial loads in the lungs compared to those in untreated control mice (85). Finally, as also seen in cancer, a reduced number of circulating iNKT cells has been reported in patients suffering from TB. In addition, patients undergoing an active TB infection showed even lower iNKT cell counts than patients with latent TB (86).
A dual role has been described for iNKT cells during mycobacterial granuloma formation (87). Infection with M. tuberculosis has been reported to induce the formation of granuloma-like lesions, in which iNKT cells have been detected in abundance (87). Accordingly, when Jα18KO mice were infected, no granuloma formation was detected, further supporting the role of iNKT cells in this process (87). Remarkably, this study used a recombinant M. tuberculosis with a modified cell wall, from the strain H37rv, which does not express any proteins in its membrane. Therefore, this recombinant M. tuberculosis strain is likely to expose higher lipid amounts, which might have induced higher iNKT cell activation rates (87). It has also been reported that iNKT cells are able to recognize and kill M. tuberculosis-infected macrophages, secreting high levels of IFN-γ during this process. M. tuberculosis-infected macrophages were able to secrete IL-12p40 and IL-18, further activating iNKT cells (88). As M. tuberculosis-infected macrophages have been described to be the initiators of the granuloma formation mechanism, these observations suggest that iNKT cells might protect against granuloma formation. No further information has been published to date, and so the contribution of iNKT cells in this phenomenon remains to be elucidated (Table 1 and Fig. 5A). Overall, the data suggest that iNKT cells contribute to the immune protection against TB, as the absence of these cells seems to be detrimental to the resolution of the disease (70, 79–88).
Influenza virus.
Influenza A virus (IAV) is one of the major causes of respiratory diseases worldwide, with significant zoonotic capacity that leads to high rates of mutation for this virus (89). The role of iNKT cells during IAV infections has been reported by several authors, generally with protective characteristics. For instance, it has been described that treatment with αGalCer promotes early enhanced innate responses, with no effect on T cell activation, reduced viral titers, and less severe weight loss (90). Accordingly, iNKT cells have been shown to be required for the inhibition of the expansion of myeloid-derived suppressor cells (MDSCs), as the absence of iNKT cells causes an increase in MDSC proliferation (91). Increased MDSC proliferation suppresses IAV-specific immune responses, leading to higher viral titers and increased mortality in CD1d-deficient mice. Remarkably, the adoptive transfer of iNKT cells to CD1d-deficient mice prevented the suppressive effects of MDSCs, further supporting the contribution of iNKT cells for an effective response against IAV (91).
As mentioned above, the antiviral B cell response can be enhanced by the IL-4 produced by activated iNKT cells as part of the general innate/adaptive immune regulatory mechanism (60). These cells (both NKT cells and B cells) must be located in the intrafollicular spaces of the lymph nodes to induce this IL-4-mediated B cell activation, promoting the proliferation of extrafollicular plasma cells, secretors of low-affinity antibodies (Fig. 4) (60). Therefore, this mechanism may play a fundamental role mounting an adequate immune response against IAV. On the other hand, it has been observed that a PD-L1 deficiency renders mice less susceptible to IAV infection (92). While stimulation via PD-L1 negatively regulated IAV clearance, PD-L2 engagement contributed to reducing the exacerbated inflammation and prevented some of the severe symptoms of the disease from occurring (92). Several studies have suggested a protective effect of iNKT cells during immunization against IAV. This protection is usually achieved by administering αGalCer as an adjuvant in the vaccine formulation (93–95). In summary, infection by IAV seems to be controlled by iNKT cells, as these cells seem to protect against the infection of this pathogen (Table 1 and Fig. 5A).
Cryptococcus neoformans.
Cryptococcus neoformans is one of the leading pathogens responsible for lung, liver, and cerebral mycotic infections, which are especially prominent in (but not limited to) immunocompromised hosts (96, 97). Little is known about the role of iNKT cells during the clearance of C. neoformans infection, but early studies have suggested that these cells are crucial for an early immune response against this pathogen. Unfortunately, there are virtually no recent studies evaluating the contribution of iNKT cells to the immune response triggered upon C. neoformans infection.
It was initially shown that stimulation with αGalCer promoted an initial increase in IFN-γ in the sera of C57BL/6 mice intravenously infected with C. neoformans, which was associated with a decrease in the CFU counts in the lungs and spleens of these animals (98). Considering that C. neoformans is a facultative intracellular pathogen, IFN-γ secretion is considered a requirement for a proper immune response against this fungus (99). It was determined that the cellular sources of plasmatic IFN-γ after αGalCer administration were both iNKT cells and transactivated NK cells at early infection stages (98). In contrast, T cells take over during later stages of infection, since CD4+ KO mice showed an early increase in plasmatic IFN-γ by day 3 following infection but virtually no IFN-γ secretion by day 7 (98). Moreover, administration of αGalCer to Jα18KO mice failed at promoting an early secretion of IFN-γ and at reducing the counts of fungal CFU after infection, suggesting that activated iNKT cells significantly contribute to the early response against this pathogen and promote a TH1-polarized T cell response (98). By triggering this type of immunity, iNKT cell activation plays a role in the decrease of the fungal count. It is interesting to note that Jα18KO mice that did not receive αGalCer showed no differences in disease severity in comparison to that of wild-type (WT) mice, suggesting that iNKT cells might not become activated during an intravenous C. neoformans challenge, despite their potential protective role. However, because C. neoformans is an airborne pathogen (99), a direct intravenous challenge might not represent a natural infection for evaluating the contribution of NKT cells during the disease caused by this pathogen.
A follow-up study described that after an intratracheal C. neoformans infection, the population of CD3+/NK1.1+ cells (defined as NKT cells) increased in the lungs (100). Such accumulation was preceded by, and in part dependent on, the production of CCL2 in the lung, which was detected since day 1 p.i. and peaked at day 3 p.i. (100). Interestingly, Jα18KO mice showed no increase in IFN-γ secretion at early time points of infection and exhibited higher fungal loads in the lungs, suggesting that lung NKT cells were protective during C. neoformans infection and responsible for the early secretion of IFN-γ (100). Moreover, given that NKT cells were recruited to the lung in the absence of αGalCer stimulation, these data suggest that NKT cells are beneficial for the host during a natural infection with C. neoformans.
Later on, it was shown that 6- to 7-week-old immunized C57BL/6 mice failed to resolve intratracheal C. neoformans lung infections compared to 15-week old immunized mice (101). Moreover, passive transfer of thymocytes from 10-week-old to 6-week-old mice promoted an increase in delayed-type hypersensitivity (DTH), whereas transfer of thymocytes from 2-week-old mice did not. Since DTH is one of the responses usually evaluated to determine cell-mediated immunity against an antigen, and cell-mediated immunity is key for the clearance of C. neoformans, an increased DTH response is expected to achieve clearance of this microorganism (102). Given that iNKT cells mature in the thymus, it is necessary to point out that the maturation stage of thymic iNKT cells has a direct impact on their functional features. Quite consistently, IL-4 secretion is higher in immature iNKT cells and the capability of secreting IFN-γ is gained through NK1.1 upregulation during maturation in mice (103, 104). Remarkably, it was found that transfer of NK1.1-depleted thymocytes from 10-week-old mice did not increase DTH magnitude (101). It was also shown that the number of iNKT cells increased as mice aged and that the development of these cells increased as well through a process that involves 4 stages of maturation (stages 0 to 3) (105, 106). Previous studies have suggested that iNKT cells are immature at birth, and in order to achieve full functionality, they need to be primed (107). Given that there is recent evidence of a thymic-maturing NK cell subset (with high cytokine secretion potential) that is developmentally unrelated to T cells (108, 109), depletion of total NK1.1+ cells results in both NK cell and iNKT cell depletion from thymocytes. Thus, the effects of iNKT cell depletion are indistinguishable from the effects of NK cell depletion in that study, and so it cannot be asserted that the lack of increase in DTH in transferred mice was due to a lack of only mature iNKT cells. Despite the fact that this study suggests a possible role of iNKT cells during C. neoformans infection, specific depletion of iNKT cells prior to thymocyte transference would be required for the authors to assert that iNKT cells are responsible for this DTH increase.
Altogether, these reports indicate that iNKT cells participate in an early response against pulmonary infections of C. neoformans (Table 1 and Fig. 5A). However, more studies regarding the role of iNKT cells should be performed, especially given the lack of novel and relevant information in this regard.
iNKT Cell Contribution to Immunity against Infectious Agents Causing Gastrointestinal Disease
Salmonella enterica.
Salmonella enterica serovar Typhimurium is a bacterial pathogen that causes gastroenteritis in humans (110, 111). In mice, S. Typhimurium causes enteric fever, with symptoms similar to the ones seen when Salmonella enterica serovar Typhi infects humans (110, 111). In the first 24 h of infection with S. Typhimurium, activation of most of the CD1d-restricted T cells is achieved in mice. These T cells are one of the first lymphocytes to produce IFN-γ (112). As seen during in vitro assays, cocultures of DCs previously treated with extracts from S. Typhimurium induced the secretion of IFN-γ by iNKT cells through a CD1d-dependent manner (113). The TLRs expressed by DCs could detect lipopolysaccharide (LPS) from S. Typhimurium, promoting the secretion of IL-12. This IL-12, along with the stimulation of glycosphingolipid isoglobotrihexosylceramide (iGb3) bound to CD1d, induced the secretion of IFN-γ by iNKT cells (113). Remarkably, depletion of iNKT cells from mice did not increase susceptibility to an infection with S. Typhimurium (113). Finally, iNKT cells can be activated without the need of CD1d or endogenous self-lipids via cytokine-mediated activation (114). Considering these data, it can be suggested that S. Typhimurium can activate iNKT cells through a TCR/CD1d-independent manner and that the presence of these cells may not have an impact on the susceptibility of mice to S. Typhimurium infections (Table 1 and Fig. 5A).
Listeria monocytogenes.
Listeria monocytogenes is the microorganism responsible for listeriosis, a disease that is among the most severe caused by contaminated food (115). Few reports have addressed the effect of iNKT cells during listeriosis. Upon infection of mice with L. monocytogenes, Vα14+ iNKT cells mount an early response against this pathogen, secreting IFN-γ (116). The memory response promoted by iNKT cells upon L. monocytogenes infection remains controversial. Memory iNKTFH cells are found among the different polarized profiles of iNKT cells (116, 117). iNKTFH cells can promote a memory response through their interaction with DCs or memory B cells. However, Vα14+ iNKT cells were unable to mediate a memory response during L. monocytogenes infection (116, 117). Interestingly, in the absence of IFN-γ or the IFN-γ receptor, mice had no protection against this pathogen (118, 119).
It has been shown that the treatment of mice with an anti-CD1 antibody interferes with the activation of iNKT cells, leading to an increased survival of L. monocytogenes infected mice. This treatment also resulted in increased production of TNF-α, IL-12, and IFN-γ and decreased secretion of TGF-β2 (120). TGF-β is a crucial cytokine for the development of iNKT cells and their differentiation into a regulatory profile (121, 122). TGF-β also plays a significant role in regulatory responses against other intracellular pathogens such as IAV, M. tuberculosis, and Chlamydia muridarum, because larger quantities of these pathogens are detected when this cytokine is present (123–125). Moreover, TGF-β can regulate the immune response by inhibiting the secretion of several cytokines such as TNF-α, IL-12, and IFN-γ. Importantly, iNKT cells are a significant source of TGF-β; therefore, iNKT cells might play a significant role in the regulation of the immune response elicited during L. monocytogenes infections (126, 127). A new regulatory population of CD11b+ iNKT cells has been reported, obtained from the livers of mice upon infection with L. monocytogenes (128). This population produced low levels of soluble TGF-β1 (along with low levels of IFN-γ, IL-4, and IL-10) but high levels of membrane-bound TGF-β1 (mTGF-β1) (128). The cell-to-cell interaction between iNKT cells and either CD4+ or CD8+ T cells, via mTGF-β1 expressed by NKT cells, prevented the proliferation of these T cells but did not alter their activation or effector function (128). It is possible that the increment of mTGF-β1 on these iNKT cells polarized them toward a regulatory profile, similar to the one described for NKT17 cells. Both CD11b+ mTGF-β1+ NKT cells and NKT17 cells seem to be playing similar regulatory roles during pathogenic infections. These regulatory profiles inhibit the proliferation of T cells and therefore impair the immune response against pathogens such as L. monocytogenes (128). Consequently, the microorganisms keep spreading without resistance in these mice, and TGF-β plays a negative role in the control of the pathogens. Despite all this, further studies are still required to completely clarify the role of TGF-β1 secreted by iNKT cells in the infection by L. monocytogenes.
It has been reported that administration of αGalCer to mice elicited a protective profile upon infection with L. monocytogenes, which was mediated by IFN-γ-secreting iNKT cells. The secretion of this cytokine induced the activation of macrophages, the ones responsible for killing the bacterium (129). Therefore, iNKT cells in mice are relevant for the control of L. monocytogenes, since they produce IFN-γ, while the absence of this cytokine renders mice more susceptible to an infection with this pathogen (Table 1 and Fig. 5A).
iNKT Cells Play Protective Roles against Infectious Agents Causing Hepatic Disease
Hepatitis B and C viruses.
Viral hepatitis is one of the most critical public health burdens worldwide. Both hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatic diseases such as liver fibrosis and cirrhosis. HBV and HCV also increase the risk of suffering from hepatocellular carcinoma (130–132). In the liver, iNKT cells are the most abundant cell type among the intrahepatic lymphocytes, reaching levels up to 20% to 30% in mice (133).
The role of iNKT cells has been described for HBV transgenic mice (capable of being infected by the virus) (133–135). Administration of αGalCer activates iNKT cells in the livers of these mice, and viral replication is inhibited (133). The mechanism suggested for this inhibition is through the secretion of type I and II IFN (IFN-α/β/γ) (Fig. 5A) (133). Decreased frequencies of iNKT cells in the liver, affecting the secretion of IFN-γ and IL-4, was also described (133). HBV infection decreased CD28 expression and increased PD-1 expression by iNKT cells, which could be modulated by the administration of αGalCer (136). This capacity of modulating the response suggests that αGalCer has a dual role for iNKT cells, as it can induce either an anergic state or their activation. The secretion of IFN-γ was increased upon the blockage of PD-1/PD-L1 and the engagement of CD28 by CD80 on iNKT cells (136). Viral replication was also decreased, suggesting a mechanism that involves PD-1/PD-L1 and CD28/CD80 in the modulation of HBV infection mediated by iNKT cells (Fig. 5A) (136).
In human patients with chronic hepatitis B virus infection, the role of iNKT cells is uncertain, as studies have reported opposite results (132, 137–139). The frequency of circulating iNKT cells was decreased in patients with chronic hepatitis B virus infection compared to that in inactive HBV carriers and healthy controls. Moreover, the population of CD4− NKT cells was the most affected by chronic infection (132). Circulating iNKT cells expressed higher levels of CCR5 and CCR6 than the other cells from these patients. No differences were found in the secretion of IFN-γ and IL-4 by iNKT cells (132). Considering this, it is suggested that the low numbers of circulating iNKT cells are due to iNKT cell migration to the liver in response to a gradient of CCL5 (132). Another report analyzed peripheral iNKT cells in patients with chronic hepatitis B virus infection, showing different results (138). Authors divided chronic hepatitis B patients into three different groups according to their phase of the disease: immune tolerance phase (IT), in immune clearance phase (IC), or inactive carrier phase (IA) (138). iNKT cells were decreased only in the chronic hepatitis B IT group and were increased in the chronic hepatitis B IC and IA groups. The percentage of circulating iNKT IFN-γ+ cells negatively correlated with the HBV viral load (138). The chronic hepatitis B IT group exhibited lower percentages of iNKT IFN-γ+ cells than the other groups and the healthy controls. The percentages of circulating iNKT IL-4+ cells positively correlated with serum HBV viral loads and alanine aminotransferase levels. Increased percentages of iNKT IL-4+ cells were observed in the chronic hepatitis B IT group (138). In conclusion, while iNKT IFN-γ+ cells are beneficial for viral clearance, iNKT IL-4+ cells promote hepatic damage (138). Therefore, depending on the disease stage, the role of iNKT cells in chronic hepatitis B virus infection may be differentially modulated, with tolerant patients showing decreasing frequencies of iNKT cells (Fig. 5).
The role of iNKT cells during HCV infection is also controversial and poorly described. It has been shown that the number of circulating iNKT cells (Vα24+ Vβ11+) was not decreased in patients with HCV infection compared to that in healthy controls (140). Administration of an antiviral treatment had no effect on iNKT cell numbers, and no differences were found between patients who responded to the antiviral treatment and nonresponders (140). Contrarily, HCV-infected patients exhibit lower frequencies of circulating iNKT cells (Vα24+ Vβ11+) than healthy controls (141). The discrepancy between these reports may be due to the strategy used for the determination of the NKT cell population, i.e., the use of tetramer for their characterization instead of phenotyping by using Vα24+ Vβ11+ markers, which varies among studies.
Dengue virus.
Dengue virus (DV) is the most significant viral illness affecting humans that is transmitted by a mosquito. Infections with DV can lead to dengue fever, its most common manifestation, and in some worst-case scenarios, it can lead to dengue hemorrhagic fever which turns into dengue shock syndrome, resulting in the death of infected subjects (142). This disease causes such a burden on the population worldwide that is considered a global economic and health problem (143). The role of iNKT cells during infections with DV has been studied in both humans and animal models. Infection with DV promotes the activation of iNKT cells (144–146). In a human study, DV infection did not only activate iNKT cells but also stimulated the expression of CD1d in T cells (146). In the murine model, iNKT cells were necessary to control viral replication, as they recruited mast cells that helped in the clearance of the virus (144). Conversely, mice depleted of iNKT cells (Jα18−/−) challenged with DV were more resistant to lethal infections than WT mice (145). Also, Jα18−/− mice exhibited less systemic and local inflammatory responses. It can be suggested that iNKT cells were not necessary to control the primary DV infection, but they had a noticeable decisive role in the pathogenesis of severe dengue illness (145). These data suggest that the role of iNKT cells against DV is most likely protective, as these cells help to achieve the clearance of the virus. While iNKT cell depletion decreases the severity of the disease (therefore inducing damage when present), it may be worth noting that, as stated previously, this damage may also be caused by other components of the immune response. Antibodies or innate cells, rather than iNKT cells themselves, may be considered among these other components, although further studies are required to elucidate this point.
iNKT Cells Play Important Roles against Infectious Agents Causing Blood and Systemic Diseases
Borrelia burgdorferi.
Borrelia burgdorferi is the bacterium responsible for Lyme disease, and if this disease is not treated early, it can develop into meningitis, arthritis, and carditis (147). The roles of iNKT cells and CD1d have been studied and characterized in mouse models (148–153). It appears that CD1d is necessary to resist infections caused by this pathogen, as its absence increased the severity of the disease (148). Upon infection with B. burgdorferi, iNKT cells are activated, stimulating the production of IFN-γ and, consequently, decreasing the severity of the disease (Fig. 5A) (149). B. burgdorferi possesses two glycolipids in its membrane consisting of α-galactosyl-diacylglycerol, molecules that can activate both human and mouse iNKT cells (150, 151). These glycolipids are named B. burgdorferi glycolipid 1 (BbGL-I) and glycolipid II (BbGL-II) (Table 1). BbGL-II can activate Vα14+ iNKT cells in a way that is independent of the engagement of the TLRs expressed by these cells (151). It has been suggested that B. burgdorferi can modify these glycolipids (still allowing these glycolipids to bind to CD1d but losing the capability of engaging with the invariant TCR of iNKT cells) in order to prevent iNKT cell activation (152). A similar suggestion was made a few years later when it was reported that iNKT cells exhibit a high specificity for some fatty acids within these glycolipids. These data suggest that the alteration of fatty acid chains from the glycolipids expressed by B. burgdorferi is a possible mechanism of immune evasion acquired by this microorganism (153). Therefore, iNKT cells play a protective role in the disease caused by B. burgdorferi, as these cells can be activated by recognizing B. burgdorferi glycolipids, leading to the secretion of IFN-γ, which will helps to control the infection with this pathogen (150, 151).
EXACERBATION OF THE IMMUNE RESPONSE OR CONTROVERSIAL ROLE OF iNKT CELLS DURING INFECTIOUS DISEASES
Despite the beneficial role described for iNKT cells in the previous section, several other reports have been published showing evident downsides for their activation and even their presence. In the following section, we will describe the current knowledge about the negative or controversial role of iNKT cells during pathogenic infections (Table 1 and Fig. 5B).
iNKT Cells Exhibit Controversial and Uncertain Roles in Pulmonary Infection
Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a known opportunistic pathogen, which means that this microorganism can infect when the immune response of the host is compromised (154). This bacterium is highly resistant to antibiotics and causes community-acquired pneumonia, therefore being a major health problem (154–156). The production of IFN-γ by iNKT cells is critical to initiate the inflammatory response against P. aeruginosa (157). It has been shown that upon infection with P. aeruginosa, the capacity of CD1d−/− mice to kill this pathogen was impaired compared to that of WT mice. This impairment was correlated with a decrease of macrophage inflammatory protein-2 (MIP-2, also known as CXCL2) and neutrophil infiltration (158). The treatment of WT mice with αGalCer prior to the infection with P. aeruginosa promoted the clearance of this pathogen and the secretion of IFN-γ by iNKT cells. The increased secretion of IFN-γ increased the phagocytic capacity of macrophages toward P. aeruginosa (158). Therefore, treatment with αGalCer promotes a protecting environment against the development of severe pneumonia caused by P. aeruginosa, suggesting that iNKT cells and alveolar macrophages are possible cell targets for therapeutic applications (158). Conversely, another report shows that infections with P. aeruginosa in Jα18−/− and CD1d−/− mice result in similar bacterial loads and neutrophilic responses among KO and WT mice. These did not induce the clearance of the pathogen nor enhanced the neutrophilic response. However, treatment with αGalCer increased the secretion of IFN-γ (159). Though there is still debate whether iNKT cells are essential for the protection against P. aeruginosa, it is well known that the IFN-γ secreted upon infection is produced by iNKT cells (Table 1 and Fig. 5B).
Epidemic coronaviruses SARS-CoV and SARS-CoV-2.
Viruses from the Coronaviridae family are enveloped, single-stranded, nonsegmented, positive-sensed RNA viruses. This family of viruses is very diverse and comprises 4 genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (160). Each of these genera encompasses many species. Although many coronaviruses are the etiological agents of common colds, epidemic coronaviruses (particularly betacoronaviruses) have been identified over the last 2 decades (161, 162). Such is the case of the severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the closely related SARS-CoV-2, which were responsible for pandemic outbreaks in 2002 and 2019–2020, respectively (160, 162).
The role of iNKT cells in the pathogenesis of the disease caused by these aggressive respiratory viruses is far from being completely understood. To our knowledge, there is only one study exploring the role of NKT cells in mice in in vivo schemes of infection with SARS-CoV (163). However, the only result regarding NKT cells (defined as CD3+ CD49b+ cells) in that article shows that these cells are more abundant in the lungs of infected mice by 7 days p.i. (163). Unfortunately, the article did not explore further the role of NKT cells in the pathogenesis or disease resolution during SARS-CoV infection, and so the role of these cells remains unclear.
A very recent preprint (not-yet peer reviewed) evaluates the role of iNKT cells in bronchoalveolar lavage fluid (BALF) and peripheral blood from 3 patients during the acute and convalescence phases of COVID-19, due to SARS-CoV-2 infection (164). Most T cells in the BALF from these patients during the acute phase of infection had an NKT-like profile, representing approximately 90% of the BALF-infiltrating T cells. NKT-like T cells also appeared to represent a significant proportion of the T cells found in the BALF from convalescent patients. Moreover, the numbers of circulating iNKT cells in peripheral blood samples from acute and convalescent patients were 6.4 and 2.5 times higher than in healthy controls, respectively, and peaked by 7 days after the onset of symptoms (164). The abundance of iNKT cells (defined in this study as CD3+ cells that also stained positive for a CD1d tetramer loaded with PBS57, an αGalCer analog) was also increased in the peripheral blood samples from these three patients. However, more specific aspects of iNKT cells, such as iNKT cell polarization and cytokine secretion, were not evaluated. No similar studies assessing the role of iNKT cells during SARS-CoV-2 infection have been published up to date (164).
The tendency of iNKT cells to increase their numbers during epidemic coronavirus infections is certainly intriguing and may constitute a new therapeutic target. The potentially pivotal role of iNKT cells during these infections, especially during SARS-CoV-2 infection, is definitely worth further study (Table 1 and Fig. 5B).
Human respiratory syncytial virus.
Human respiratory syncytial virus (hRSV), recently renamed human orthopneumovirus (165), is the leading cause of acute lower respiratory tract infections worldwide, affecting mainly (but not exclusively) children, the elderly, and immunocompromised patients (166). hRSV has been described to induce exacerbated inflammation and infiltration of immune cells into the lungs (166). Accordingly, enhanced secretion of inflammatory cytokines (such as IL-6) and decreased secretion of antiviral cytokines (such as IFN-γ) impair the clearance of this virus (166–168).
To date, little has been described regarding the role of iNKT cells in the infections caused by hRSV. It was reported that WT mice stimulated with αGalCer exhibited increased numbers of CD8+ T cells, increased secretion of IFN-γ, reduced illness symptoms (such as weight loss), and enhanced viral clearance capacities compared to those of CD1d-deficient mice (169). These measurements were performed at day 7 p.i. and suggested a protective role of iNKT cells against this virus. However, this report also showed increased viral loads in mice treated with αGalCer compared to those in vehicle-treated mice (169). Conversely, some years later, it was described that sensitization of newborn mice with αGalCer and a subsequent infection with hRSV rendered these pups more susceptible to exacerbated hRSV infections during adulthood, with symptoms similar to that of an asthma-like pathology (170). This report suggests that iNKT cells may play a negative role in modulating this disease, as subsequent exposures to this virus led to enhanced disease parameters.
Recently, a controversial role for iNKT cells during hRSV infection was reported (171). Through the use of CD1d-deficient BALB/c mice, it was shown that no differences were detected in weight loss, cells infiltrating to the lungs, histopathological scores, and viral loads compared to those in mock-treated mice by day 3 p.i. These parameters (weight loss, cells infiltrating to the lungs, histopathological scores, and viral loads) were increased in hRSV-infected WT mice, as commonly reported for this virus. IL-2- and IFN-γ-secreting iNKT cell numbers were also reduced in hRSV-infected mice compared to those in mock-treated mice. An increase in the concentration of IFN-γ was detected in the BALF of hRSV-infected CD1d-deficient mice compared to that in hRSV-infected WT mice. Although other cytokines were measured, such as IL-5, IL-6, IL-1β, and IL-10, no statistical differences were detected in these. Altogether, these results suggest that iNKT cells play a negative role in hRSV disease. As already mentioned, most of these results were measured by day 3 p.i., partially explaining the differences seen with the first study.
The latter study also has some interesting in vitro results, expanding further the understanding of the role of iNKT cells in hRSV infections (171). IL-2 secretion was measured in cocultures of iNKT cells in hybridoma with DCs (either infected or not with hRSV) upon stimulation with αGalCer. A significant decrease in the secretion of IL-2 was detected in the cocultures with hRSV-infected DCs compared to that with noninfected DCs. This reduction suggests that hRSV might be capable of impairing iNKT cell function, as also reported for T cells (172). The coculture of iNKT cell hybridomas with lung cell suspensions from hRSV-infected mice induced a decrease in the surface expression of CD1d on CD11b+ DCs, alveolar macrophages, and epithelial cells compared to that in uninfected mice. This decrease in the expression of CD1d suggests that infection with hRSV modulates the expression of this receptor, which in turn, results in differential activation of iNKT cells. Considering these reports, the effective role of iNKT cells during hRSV infection remains controversial, and further studies are still required to determine their role in this disease (Table 1 and Fig. 5B).
Human metapneumovirus.
Human metapneumovirus (hMPV) is another highly prevalent respiratory virus that causes severe diseases in children, the elderly, and immunocompromised patients. This virus exhibits remarkable similarities with hRSV, also inducing a TH2-biased immune response, increasing the infiltration of immune cells into the lung, and inducing the secretion of proinflammatory cytokines (168, 173).
The recent report described in the previous section evaluating the role of iNKT cells in hRSV also evaluated the role of these cells during hMPV infections. Currently, this is the only study that considers iNKT cells and hMPV infections (171). No differences were found between WT and CD1d-deficient mice in the disease parameters measured (those were weight loss, cells infiltrating to the lungs, histopathological scores, and viral loads) upon hMPV infection. Accordingly, no differences were found in the numbers of IL-2-, IFN-γ-, and IL-4-secreting iNKT cells among WT and CD1d-deficient mice (171). Finally, no statistical differences were found in the concentrations of cytokines measured in BALF, which included IFN-γ, IL-5, IL-6, IL-1β, and IL-10. Altogether, these results suggest that iNKT cells do not play a significant role during hMPV infections, as their presence or absence has no impact on the parameters measured (171).
Despite the lack of responses in vivo, and as also seen for hRSV, hMPV seems to impair iNKT cell function in vitro. Upon coculture of iNKT cells hybridomas with hMPV-infected DCs, a decrease in the secretion of IL-2 was detected compared to that from noninfected cells (171). This reduction is in line with previous reports suggesting that hMPV is able to impair T cell activation when these cells are cocultured with hMPV-infected DCs (174). Coculture of iNKT cell hybridomas with lung cell suspensions from hMPV-infected mice induced a decrease in the surface expression of CD1d on alveolar macrophages and monocytes compared to those from uninfected mice. This decrease in the surface expression of CD1d hints that hMPV does have an impact on iNKT cells, although this may not be physiologically relevant, as no effects were seen in vivo. Further studies are still required to elicit the role of iNKT cells during hMPV infections (Table 1 and Fig. 5B).
Aspergillus fumigatus.
Aspergillus fumigatus is a ubiquitous fungus commonly associated with allergic sensitization and asthma activation in humans. It has been shown that CD1d−/− mice exhibit an impaired capacity to achieve an early clearance of A. fumigatus upon infection compared to that of WT mice, as the latter exhibited a lower fungal burden in lungs by day 7 p.i. (175). Nevertheless, both CD1d−/− and WT mice were capable of clearing the fungus eventually. Additionally, CD1d−/− mice also showed greater infiltration of monocytes, neutrophils, and DCs in their BALFs than WT mice, which probably contributed to the observed exacerbated pulmonary inflammation in the CD1d−/− mice (175). Remarkably, iNKT cells were activated by A. fumigatus and rapidly secreted IFN-γ. Interestingly, the secretion of IFN-γ derived from iNKT cells was shown to be dependent on certain β-1,3 glucans (zymosan, scleroglucan, and curdlan, molecules of nonlipidic nature that make up the fungal cell wall) that activated DCs (175). Interestingly, DCs recognized fungi through pattern recognition receptors (PRRs) such as dectin-1 (CLEC7A) and MyD88-associated PRRs (probably TLRs) and, consequently, secreted IL-12, an effect that was even more pronounced when they were cocultured with iNKT cells (175). Finally, the secretion of IL-12 by DCs was shown to stimulate iNKT cells and promote their differentiation into a beneficial, IFN-γ-producing TH1-like profile (175). These findings are consistent with previous studies showing that TNF-α, along with IFN-γ production, is critical for protection against invasive aspergillosis (176, 177). A mechanism of iNKT cell activation by glucan-activated DCs was suggested. This mechanism indicates that DCs become activated through the engagement of the TLRs and dectin-1 (expressed by these cells) with fungus-derived glucan, thereby promoting IL-12 secretion and activating iNKT cells upon recognition of self-lipids presented by the CD1d receptor on the surfaces of DCs. The recognition of fungal β-1,3 glucans by DCs may be a conserved iNKT cell-mediated response against various fungal pathogens, such as Candida, Histoplasma, and Alternaria (175).
On the contrary, iNKT cells have also been described as harmful during A. fumigatus infections, since they induce airway hyperreactivity (AHR) in BALB/c mice. Interestingly, it has been observed that asperamide B (Asp-B) (one of the glycosphingolipids exhibited in the membrane of the fungus) (Table 1) can be loaded onto the CD1d receptor and rapidly activate these cells. Remarkably, this was the first fungal glycolipid described to activate iNKT cells in a MyD88-dependent but dectin-1-independent manner, thus ruling out the involvement of β-1,3 glucan recognition during iNKT cell activation (178). These cells may play a significant role in the exacerbation of severe chronic respiratory diseases caused by A. fumigatus in humans. In vitro administration of Asp-B to human iNKT cells cocultured with DCs in vitro was able to induce the activation of iNKT cells, leading to a quick secretion of IL-4 and IL-13. Moreover, Asp-B administration to mice not only caused AHR but also enhanced the expression of IL-33 in alveolar and interstitial lung macrophages. Secretion of IL-4, IL-13, and IL-33 is characteristic of a TH2-like profile, and these cytokines are likely to enhance airway hyperreactivity (178).
More recently, it was shown that among CD1d+ human cells, cDC2s (CD1c+ DCs) exhibited the highest surface expression of CD1d and were thus the group of cells with the highest potential for activating iNKT cells. Upon coculturing iNKT cells with cDC2s, several cytokines were detected in the supernatant, such as TH1 cytokines (IFN-γ, TNF-α, and IL-2), TH2 cytokines (IL-4, IL-5, IL-6, IL-10, IL-13, among others), and growth factors (fibroblast growth factor [FGF], G-CSF, GM-CSF, and vascular endothelial growth factor [VEGF]), as well as the chemokines IL-8 and CCL5 (RANTES) (179). Moreover, when CD1d+ cDC2s and iNKT cells were cocultured with ethanol-inactivated germ tubes of A. fumigatus, reduced concentrations of GM-CSF, CCL5, and TNF-α were detected in the collected supernatants compared to those in control groups (179). Three elements should be noted of this work: first, the authors worked with human cells, therefore they address the molecular aspects of fungus-immune cell interactions better than a murine model would (179). Second, since the germ tubes were ethanol inactivated, the decrease in these three cytokine levels is contact dependent rather than because of a soluble factor or a metabolic response of the fungus in the coculturing context (179). Last but not least, lower TNF-α and G-CSF levels upon contact with inactivated A. fumigatus could be considered a strong indication of a less efficient fungal clearance in vivo (176, 177, 179, 180). However, this work lacks in vivo experiments that could support these points, and it is not possible to conclude through the methodology used by the authors if the cytokines were secreted by the DCs or by the iNKT cells.
Altogether, these data suggest that the role of iNKT cells may be beneficial or detrimental in an A. fumigatus infection depending on which antigen is presented by the CD1d molecules on DCs. Apparently, if glycosphingolipids from the fungal cell membrane are presented, secretion of TH2-related cytokines, airway hyperreactivity, and asthma-like symptoms may occur. However, if self-lipids are presented after stimulation with certain β-glucans that compose the fungal cell wall, early clearance of the fungus is achieved through enhanced IFN-γ secretion. Moreover, it seems that A. fumigatus is capable of immunomodulating the human DC-NKT cell interaction, reducing the concentration of protective cytokines against the fungus. Nonetheless, the precise role of iNKT cells during an A. fumigatus infection is still uncertain and has yet to be elucidated (Table 1 and Fig. 5B).
Negative Role of iNKT Cells in Kidney-Related Diseases
Chlamydia muridarum.
Chlamydia is a bacterium responsible for sexually transmitted diseases, mainly associated with urethritis in humans, although it can also be asymptomatic. Spreading of this bacterium can result in infertility, ectopic pregnancy, and even trachoma, which leads to blindness (181). Chlamydia muridarum is the bacterium used as a model of study for Chlamydia trachomatis, since the latter only infects humans, while the former infects mice (181). Little has been described regarding the role of iNKT cells during this disease. However, CD1d−/− mice exhibit less bodyweight loss, less pathology-associated symptoms, and lower bacterial loads during a C. muridarum infection than WT mice. Likewise, stimulation of WT mice with αGalCer during a C. muridarum infection induced a higher secretion of IL-4, a TH2-like cytokine, that exacerbated the disease, enhancing the chlamydial growth in vivo compared to that in CD1d−/− mice (181). Therefore, it can be suggested that iNKT cells play a negative role during C. muridarum infection, as their absence seems to be beneficial, while their activation with αGalCer enhances the disease (Table 1 and Fig. 5B).
Candida albicans.
Candida albicans is the fungus responsible for candidiasis, an oral and/or vaginal infection that causes itching, burning, and colonization of this pathogen in the corresponding area. C. albicans possesses various immunogenic glycolipids in its membrane, among which, cholesteryl 6′-O-acyl-α-mannoside (ChAcMan), a recently described mannosyl glycolipid, is capable of activating iNKT cells through CD1d/TCR interaction and promoting a biased IFN-γ secretion by iNKT cells (182). ChAcMan and its glucose and galactose derivatives (ChAcGlc and ChAcGal, respectively) are capable of activating iNKT cells in a dose-dependent manner, adding cholesteryl glycolipids to the list of antigens recognized by iNKT cells. Moreover, splenocytes other than iNKT cells are capable of secreting IFN-γ upon recognition of these glycolipids in a CD1d-independent manner, probably through activation of their C-type lectin receptors (CLRs) (182).
Regarding the role of iNKT cells during a C. albicans infection, it was described that the survival rate, cytokine production, and fungal clearance capacity were the same in both WT and Jα18KO mice upon challenge via retro-orbital venous plexus with this fungus. This suggests that iNKT cells may not play a significant role in the control of systemic candidiasis (183). However, a year later, the same authors published that IFN-γ-secreting iNKT cells seemed to exacerbate the disease produced by C. albicans when mice were infected by the same route of infection and also treated with αGalCer (184). Administration of αGalCer induced the secretion of IFN-γ by iNKT cells, leading to lower survival rates, higher C. albicans burden in several organs, and greater secretion of IL-6 than in control mice. This αGalCer-mediated IFN-γ increase also correlated with a decrease in the numbers of bone marrow and circulating neutrophils, one of the primary cell types responsible for the clearance of this fungus. Remarkably, administration of αGalCer to IFN-γ KO mice did not cause disease exacerbation compared to that in WT mice (184). Moreover, there was no reduction in the numbers of bone marrow or circulating neutrophils upon administration of αGalCer to these IFN-γ KO mice infected with C. albicans, suggesting that the observed decrease in the numbers of neutrophils is dependent on IFN-γ (184). The observed decrease in neutrophil numbers is probably dependent on the IFN-γ-secreting iNKT cells, since these changes were mediated by αGalCer administration. Therefore, iNKT cells may play a detrimental role during C. albicans systemic infection (184). However, since neutrophil responses to αGalCer in C. albicans-infected Jα18/IFN-γ double KO mice were not evaluated, this cannot be ascertained and has yet to be demonstrated (184). It can be presumed that IFN-γ led to an inhibition of neutrophil biogenesis, although the presence of neutrophils in infected organs was not evaluated. The lower numbers of circulating neutrophils might be related to the migration of these cells into the infected organs, where they rapidly die (184). Accordingly, elevated rates of neutrophil death could demand an accelerated rate of neutrophil biogenesis in the bone marrow, which would appear depleted of neutrophils, as these cells would rapidly exit and migrate to the site of infection. Altogether, this study lacks the necessary fundamental controls to soundly conclude that IFN-γ-secreting iNKT cells are responsible for disease exacerbation and the decrease of neutrophils in the bone marrow and blood. However, these results suggest that activation of iNKT cells would not be desirable in the context of C. albicans infection (184).
It was recently reported that mice are more susceptible to C. albicans infection upon activation of iNKT cells (185). Jα18KO mice are more resistant to C. albicans intraperitoneal infection than WT mice (185). Moreover, treatment of WT mice with αGalCer rendered them even more susceptible to C. albicans infection than Jα18KO mice. Accordingly, the fungal burden decreased in several organs, while neutrophil recruitment increased in Jα18KO mice compared to that in WT mice (185). Remarkably, the levels of IL-10 increased in WT mice during C. albicans infection compared to those in Jα18KO mice, suggesting that iNKT cells play a role in modulating the secretion of this cytokine. When Jα18KO mice were stimulated with exogenous IL-10 or passively transferred with iNKT cells, their susceptibility to C. albicans infection was increased, indicating that these cells and this cytokine seem to play a significant role in the exacerbation of candidiasis (185). Likewise, when Jα18KO mice were passively transferred with iNKT obtained from IL-10 KO mice, this increased susceptibility was not detected (185). Apparently, iNKT cells enhanced C. albicans infection through secretion of IL-10, which might have reduced neutrophil and macrophage recruitment to the infected organs. This phenomenon could explain why iNKT cell-deficient mice fared better than WT mice and why adoptive transfer of iNKT cells from IL-10-deficient mice to Jα18KO infected mice produced higher resistance to C. albicans infection than in mice transferred with iNKT cells derived from WT mice. However, more experiments are required to soundly propose this, such as demonstrating IL-10 secretion by iNKT cells during C. albicans infection and showing that the secretion of this (or other iNKT cell-derived cytokines or chemokines) decrease neutrophil and macrophage infiltration to infected organs. All these data seem to indicate that iNKT cells do exacerbate the disease induced by C. albicans, despite initial reports suggesting they lack a role (Table 1 and Fig. 5B).
Controversial or Unclear Role of iNKT Cells in Blood and Systemic Infections
Human immunodeficiency virus.
Human immunodeficiency virus (HIV) is still one of the most relevant public health problems, and its prevalence is increasing worldwide (186). HIV-1, compared to HIV-2, is more easily transmitted and exhibits a higher genetic variability (186). Transmission of this virus is achieved through the mucosal surfaces of genitals and intestinal tracts, where it crosses the epithelium to reach its target cells, commonly, activated CD4+ T cells (186, 187). HIV-1 can also infect other cell types such as monocytes, macrophages, and DCs, all of which are CD1d-expressing APCs (188). The role of the iNKT cells in the pathogenesis of HIV has been thoroughly described.
One study analyzed blood samples of 50 HIV-1-positive patients and found a reduction in the numbers of circulating Vα24+ Vβ11+ iNKT cells compared to that in healthy controls (189). No differences were found in the numbers of Vα24+ Vβ11− NKT cells or Vα24− Vβ11+ NKT cells between these groups. Patients receiving highly active antiretroviral therapy (HAAT) exhibited similar numbers of circulating Vα24+ Vβ11+ iNKT cells as healthy controls (189). This phenomenon could not be associated with direct HIV infection of iNKT cells. Since iNKT cells express CD4, the susceptibility of these cells to infection with HIV-1 has been analyzed (190). iNKT cells were isolated and enriched from peripheral blood mononuclear cells (PBMCs) from healthy donors and then expanded in vitro. These expanded iNKT cells expressed high levels of CCR5, the coreceptor for HIV-1 infection (190). CCR5-expressing iNKT cells also expressed CXCR6 and CXCR3 while expressing lower levels of CXCR4. Approximately 50% of the CD4+ iNKT cells expressing CCR5 and CXCR4 were infected by an R5-tropic HIV-1 (190). The number of circulating iNKT cells in patients infected with HIV-1 were decreased, which is consistent with the fact that CD4+ NKT cells are susceptible to infection. However, no explanation was found for the lower number of CD4− iNKT cells from HIV-1-infected patients. The authors suggest that this subset of iNKT cells may be activated by antigens or cytokines, inducing their apoptosis (190). Interestingly, it has been described that the number of circulating iNKT cells can be restored with HAAT in combination with IL-2 treatment for at least 12 months (191). This recovery of iNKT cells may be accomplished by other cell types (such as DCs) that are responsible for the activation of the former rather than a direct effect of IL-2 on iNKT cells (191).
The function of iNKT cells during HIV-1 infection has also been defined. The numbers of Vα24+ CD161+ iNKT cells were inversely correlated with viral loads (192, 193). Blood samples from 75 patients confirmed for HIV-1 infection were used for the characterization and the performance of functional in vitro experiments of iNKT cells. Approximately 89% of the Vα24+ CD161+ iNKT cells were Vβ11+ cells, and approximately 95% of the Vα24+ Vβ11+ cells were CD161+ NKT cells (193). During the acute phase of HIV-1 infection, the frequencies of the CD161+ iNKT cells and CD161+ CD4+ iNKT cells were decreased compared to that in healthy controls. These frequencies were similar after 1 year of HAAT treatment. The function of iNKT cells from HIV-1 patients was impaired compared to those in healthy controls, most likely due to the lower secretion of IFN-γ and IL-4 upon stimulation with αGalCer (193). Remarkably, HAAT treatment had a positive impact on restoring the function of iNKT cells, increasing IFN-γ and IL-4 to the levels detected in the healthy controls (193).
Regarding the relevance of the iNKT cells during HIV-1 infection, this virus possesses several molecular mechanisms to prevent antigen presentation through the CD1d molecule. An example of this is the viral protein U (Vpu), an oligomeric type I integral membrane protein with two described functions (188): it mediates the degradation of the CD4 molecule, and enhances the release of progeny virions produced from infected cells (188). HIV-1-infected DCs express lower levels of CD1d on their surfaces than mock-treated DCs. This lower expression of CD1d seems to alter the normal activation of iNKT cells. Vpu was found to interfere with CD1d in HEK293T cells, blocking the transit from the early endosomal compartment to the late endosomal/lysosomal compartment (188). This blockage could be affecting the expression of CD1d on the surfaces of DCs, altering antigen presentation and, therefore, iNKT cell activation (Table 1 and Fig. 5B).
Leishmania spp.
Leishmania species are protozoan parasites which are the main etiological agents of leishmaniasis. This infection presents either cutaneous or visceral manifestations, with the former exhibiting a more effortless clearance, as the parasite reaches the liver and the spleen in the latter. Transmission of Leishmania is dependent on either Phlebotomus or Lutzomyia female sandflies as vectors, depending on the particular species of the parasite. While living inside the intestine of the vector, Leishmania is found in an elongated, flagellated promastigote state and reproduces by mitosis. Once mature, the promastigotes migrate to the proboscis of the sand fly and infect the host upon biting. Once in the bloodstream, promastigotes can infect macrophages if they are engulfed. Inside the macrophages, promastigotes turn into amastigotes, which are smaller, nonflagellated, and rounded. These amastigotes can withstand the acidic environment of the phagolysosome inside the macrophages and multiply by mitosis, eventually bursting out of these cells, and are released into the bloodstream, where they are capable of infecting other macrophages (194).
The role of iNKT cells in Leishmania infections is controversial, and apparently factors such as the particular Leishmania species, the site, and the dose of the infection seem to play a role when defining whether iNKT cells are beneficial or detrimental to the disease prognosis. Moreover, the particular mice strain used in a murine model may influence the response of iNKT cells; for instance, C57BL/6 and BALB/c mice favor TH1 and TH2 profiles, respectively, when infected with Leishmania major (195).
Leishmania donovani is one of the main causative agents of visceral leishmaniasis in humans (194). It has been shown that CD1d−/− BALB/c mice infected with 107 amastigotes showed a higher hepatic parasite burden until week 4 p.i. and higher counts of immature granuloma formations than WT mice (196). However, by week 8 p.i., both WT and CD1d-deficient mice showed very similar parasite burdens. iNKT cells characterized in these infections were activated by LPG and GIPL, which are glycophospholipids and glycoinositol phospholipids that compose the glycocalyx of Leishmania (Table 1), and this activation was IL-12 independent (196). Using Jα18−/− C57BL/6 background mice, it was also shown that iNKT cells are recruited early in the liver (197). Phenotypically, CD4+ iNKT cells were the most abundant recruited subset in WT mice. Lack of CD4+ iNKT cells in Jα18−/− mice was compensated by the recruitment of CD4+ T cells (197). Moreover, TNF-α concentration in liver extracts was significantly lower by day 15 p.i. in Jα18−/− mice, and this decrease was statistically correlated with lower counts of large granuloma formations (197). Altogether, the results from these studies suggest that iNKT cells are beneficial during an early L. donovani infection in C57BL/6 and BALB/c mouse models.
Interestingly, CD4+ CD56+ NKT cells (defined as CD3+ CD56+ cells), but not CD8+ CD56+ cells, accumulate at the site of the infection and contribute to the pathogenesis of visceral leishmaniasis in humans (198). These CD4+ CD56+ NKT cells express Foxp3 and secrete IL-10, suggesting an inhibition of the immune response against the infected macrophages (198). An autologous adoptive transfer of CD8-enriched NKT cells to visceral leishmaniasis patients diminished the parasitic burden in blood macrophages, suggesting that CD8+ NKT cells, but not CD4+ NKT cells, have a protective role against L. donovani (198). Furthermore, the differential accumulation of NKT cells reported was caused by a higher expression of CCL4 in macrophages infected by L. donovani, which in turn attracted CCR5+ cells, such as IL-10- and TGF-β-producing CD4+ CD56+ NKT cells (199). Interestingly, NKT cells from infected individuals showed an upregulation of CCR5 expression compared to that by NKT cells from healthy individuals. Furthermore, CD8+ CD56+ NKT cells from infected individuals produced higher quantities of granzyme B than CD8+ CD56+ NKT cells from healthy individuals, further supporting the notion that CD8+ NKT cells are protective against L. donovani infection (199). Finally, it was recently determined that a specific group of CD8+ NKT cells is highly cytotoxic and provides protection against L. donovani in infected patients (200).
The other principal etiological agent of leishmaniasis is Leishmania major, which commonly causes cutaneous leishmaniasis in humans. Initial reports suggest that iNKT cells are protective during leishmaniasis (201). Vα14Jα18−/− and WT BALB/c mice were subcutaneously or intravenously injected with 2.5 × 106 or 5 × 106 promastigotes, respectively. The parasitic burden in the footpads and spleens of the iNKT cell-deficient mice was significantly higher than in WT mice by day 53 post-subcutaneous infection. On the other hand, the parasitic burden was significantly higher in the iNKT cell-deficient mice up until day 50 post-intravenous infection in the spleen and up until day 25 p.i. in the liver (201). These data suggest that iNKT cells are beneficial for lessening the parasitic burden during infections of L. major. Interestingly, iNKT cells have been shown to modulate cDC1 activity during L. major infection in mice, enhancing their capacity to induce a TH1 adaptive response (202). This could be a mechanism by which iNKT cells contribute to the resolution of L. major-induced disease.
However, controversial roles for iNKT cells during leishmaniasis have also been described (203). Mice were infected intradermally in the ear with a low infectious dose of L. major promastigotes (103 promastigotes) (203). No significant differences were detected in the numbers of iNKT cells specific to PBS57 (an αGalCer analog) in the ear, lymph node, spleen, or liver up to 8 weeks p.i. (203). Since there were no significant differences in the numbers of iNKT cells recruited among BALB/c and C57BL/6 mouse strains after infection, the development of the infection was evaluated in Jα18−/− and CD1d−/− C57BL/6 mice. Both strains of KO mice had significantly smaller ear lesions from weeks 4 to 9 p.i. than WT mice. Moreover, parasite loads in the ears and spleens by week 8 p.i. were significantly lower in Jα18−/− mice than in WT mice (203). Intraperitoneal administration of PBS57 at the time of the infection enlarged the volume of the ear lesions in WT mice from weeks 3 to 15 p.i. (203). Finally, WT mice, but not CD1d-deficient C57BL/6 mice, developed a higher parasitic burden by week 8 p.i. (203). This effect was seen to be dependent of the dose and the time of administration of the parasite. Interestingly, when evaluating these responses in BALB/c mice, the effect of PBS57 was the opposite (203). When PBS57 was administered to WT mice, ear lesions were smaller and the parasitic burdens in the ear and the spleen were significantly lower by week 8 p.i. (203). This study provides a more realistic overview of what occurs in an L. major natural infection, given that the infectious dose that was used was lower than in previous studies.
Altogether, all these data show that particular species of Leishmania, as well as the specific animal model used, are of immeasurable importance when trying to make conclusions from the experiments performed. The effects attributed to iNKT cells on the development or resolution of leishmaniasis are highly dependent on the dose and the infection site. Hence, the role of iNKT cells in this disease is not yet fully understood, and it would be useful to further investigate the biases that each murine model possesses. Also, more studies using human samples are required, since the variability seen in the animal models make them a questionable model of how leishmaniasis progresses and is attacked by the immune system in humans (Table 1 and Fig. 5B).
Plasmodium spp.
Organisms from the genus Plasmodium are the main causative agents of malaria, a disease that is vectored by mosquitoes of the Anopheles genus (204). This disease is more prevalent in developing and tropical countries. In humans, most malaria infections are due to Plasmodium falciparum and Plasmodium vivax, the first one being the most common and lethal (204). Accordingly, Plasmodium berghei and Plasmodium yoelii are the most commonly used species for studying malaria in murine models (205). Plasmodium infections have two stages of development: first, a hepatocytic stage and, second, an erythrocytic stage, leading to fever, profuse sweating, vomiting, consequent dehydration, anemia, and other malaria-related symptoms (204).
The role that iNKT cells play during Plasmodium infections has only been partially characterized to date. In this line, initial reports show that stimulation with αGalCer 1 or 2 days prior to infection with P. yoelii sporozoites rendered the parasite unable to reproduce in the livers of BALB/c and C57BL/6 mice (206). When mice were infected with blood-borne forms of P. yoelii, the administration of αGalCer did not impact the viability or the replicating capacities of the parasite (206). The anti-malaria activity reported was shown to be dependent on the production of IFN-γ and to be associated with the presence of iNKT cells and the expression of CD1d (206). Treatment of KO mice (for either Vα14 or CD1d) with αGalCer prior to the infection resulted in no changes in P. yoelii rRNA levels in the liver at 42 h p.i. (206). Nonetheless, the detected parasitic burden was not higher in untreated KO mice, suggesting that iNKT cells do not play an essential role during natural Plasmodium infection. Altogether, these data suggest that early IFN-γ production by iNKT cells is desirable for the prevention of murine hepatocyte infection caused by P. yoelii sporozoites (although this does not occur naturally) and that iNKT cells may not be as relevant for the control of merozoites found in later stages of infection (206).
It has been shown that although CD1d expression is required for antiparasitic activity of CD1d-restricted iNKT cells in hepatocytes, iNKT cells are not crucial for early control of the infection in vivo (207). No significant differences in parasite burden were found in the livers of infected C57BL/6 mice after 44 h p.i. with P. yoelii (207). No significant differences were found in the parasitemia at any day until the resolution of the infection (day 25) (207). Nonetheless, iNKT cells in the livers and spleens of infected mice did secrete discrete amounts of TNF-α and IFN-γ (207). This secretion supports the notion that although iNKT cells could be beneficial during P. yoelii infections, they are not crucial for parasite control. However, they could represent an attractive clinical target for malaria treatment, since the administration of αGalCer synthetic analogs boosts Plasmodium clearance in mice through enhanced IFN-γ secretion (206, 208, 209).
iNKT cells seem to be beneficial for the humoral response against this parasite. CD1d KO BALB/c mice showed reduced splenomegaly and lower quantities of splenocytes and B cells in the spleen during P. berghei infection, up until day 7 p.i. (210). Moreover, B cell proliferation and IgM, IgG1, and total IgG antibody titers were reduced during infection with P. berghei in CD1d−/− mice, whereas IgG2a titers were more elevated. Also, IgG titers against one of the antigens of P. berghei (the glycosylphosphatidylinositol [GPI]-anchored protein MSP-119 glutathione S transferase) were reduced in CD1d−/− mice in comparison to that in WT mice, accounting for reduced antigen-specific antibody titers (210). Altogether, these data show that the CD1d receptor and iNKT cells boost humoral immunity in vivo against P. berghei infection (Table 1 and Fig. 5B).
CONCLUDING REMARKS
The immune system protects the organism by detecting and regulating danger signals, both self and exogenous signals. To achieve this, the innate and adaptive responses must work in a coordinated fashion, with each branch being responsible for protecting their own way. NKT cells are innate-like T cells capable of connecting the innate and the adaptive responses. NKT cells possess characteristics of both T cells and NK cells, such as a TCR and receptors such as NK1.1 and Ly49. Type I NKT cells (iNKT cells) express an invariant TCR that can interact with the receptor CD1d, which presents antigens of lipid/glycolipid nature on the surfaces of APCs. iNKT cells play significant roles in the modulation of both innate and adaptive responses, activating and inhibiting cell populations on both sides, secreting different sets of cytokines, and inducing the proliferation of different subsets of cells. αGalCer is the most described molecule capable of inducing the activation of iNKT cells, although several analogs of this molecule have been described. This versatility gives iNKT cells the capability to either protect or exacerbate diseases. In an immune response, this versatility can be modified by pathogens, enhancing their capacities to survive in the otherwise aggressive environment that is surveilled by the immune system, as seen for the different pathogens described above. Dual roles for iNKT cells can also be seen during the same disease, as reported for Mycobacterium, where these cells protect against the infection while also promoting the formation of granulomas. Further work is required to fully comprehend how iNKT cells can modulate all these responses and, therefore, enable us to use them as our allies for different therapeutic strategies to control pathogenic diseases.
ACKNOWLEDGMENTS
All authors listed have made substantial, direct, and intellectual contributions to the work and approved it for publication. N.M.S.G., conceptualization, writing original draft, figure design, review, editing, and revision of all versions; K.B., conceptualization, writing original draft, review, editing, and revision; G.A.P., conceptualization, writing original draft, figure design, review, editing, and revision; C.A.A., conceptualization, writing original draft, review, editing, and revision; L.J.C., reviewing, editing, and revision; A.M.K., conceptualization, revision of original draft, editing, and revision of final version.
This work was supported by the Millennium Institute of Immunology and Immunotherapy (P09/016-F and ICN09_016), CORFO grant no. 13CTI-21526/P4 and P5, FONDECYT grants 3180570 and 1190830, and CONICYT scholarship 21190183.
A.M.K. is a Helen C. Levitt Visiting Professor at the Department of Microbiology and Immunology of the University of Iowa.
We declare no conflict of interest.
Biographies
Nicolás M. S. Gálvez, MSc and PhD(c), is a doctoral student of the Molecular Genetics and Microbiology program at Pontificia Universidad Católica de Chile (2018 to 2020). He has worked with Dr. Kalergis and the Millennium Institute of Immunology and Immunotherapy since 2013. His undergraduate degree was in Biochemistry at the same university (2012 to 2017). His doctoral thesis aims to evaluate the protective role of vaccine-induced maternal antibodies in the offspring upon infection with respiratory viruses. He has also worked on vaccine prototypes against several respiratory viruses, the molecular mechanisms underlaying infections with respiratory viruses, and the roles of several cell types, such as NKT cells, during these infections. His current research interest focuses on microbiology and immunology, with a highlight on translational science, aiming to generate knowledge and therapies that may improve the life and well-being of people worldwide.
Karen Bohmwald, PhD, studied biochemistry at the Universidad Andrés Bello and did her PhD work on molecular genetics and microbiology at the Pontificia Universidad Católica de Chile (2011 to 2017). She is currently working on her postdoctoral fellowship in the field of microbiology and neuroimmunology (2018 to 2020). She has been a member of the laboratory of Dr. Kalergis since 2010, while also being a member of the Millennium Institute of Immunology and Immunotherapy. Part of her work in the laboratory of Dr. Kalergis has been focused in the role of the immune system and how infections with respiratory viruses have an impact in the central nervous system. Her main interest in this area is based on understanding how infections by respiratory viruses can generate consequences that go unnoticed at the level of the central nervous system and what the role of the immune system is in this phenomenon.
Gaspar A. Pacheco, BSc, is currently an undergraduate student of the biochemistry program at Pontificia Universidad Católica de Chile (2017 to 2020). He has been a member of the laboratory of Dr. Kalergis since 2018, where he joined the work in the field of microbiology and immunology. He has been a member of the Millennium Institute of Immunology and Immunotherapy ever since. He is currently performing experiments for his undergraduate thesis under the supervision of Dr. Kalergis, consisting of the evaluation of the humoral response elicited by vaccine prototypes against respiratory viruses. His interest in microbiology and immunology stems from the belief that the understanding of the factors that contribute to infection and immune homeostasis is critical for the development of novel and effective therapies, which represent concrete and real solutions for worldwide health issues.
Catalina A. Andrade, BSc, is an undergraduate student from the biochemistry program at the Pontificia Universidad Católica de Chile (2015 to 2020). She has worked in the laboratory of Dr. Kalergis and been a member of the Millennium Institute of Immunology and Immunotherapy since 2018. She is currently working on her thesis project, which focuses on the relationship between major respiratory viruses and the central nervous system. She has worked on various research lines during her laboratory experience, including how respiratory viruses modify immune populations in the host and the neuroreceptors in the immune populations. Her interest is in microbiology and immunology, especially in how respiratory viruses can alter both the immune system and the nervous system and the mechanism involved in this process. Elucidating this would aid in the prevention of pathologies originated by these pathogens and improve the quality of life of people.
Leandro J. Carreño, PhD, is an Associate Professor at the Institute of Biomedical Sciences at the School of Medicine of the Universidad de Chile and an Associate Investigator at the Millennium Institute of Immunology and Immunotherapy (2016 to 2020). He received his PhD training at the Pontificia Universidad Católica de Chile, by the support of Chilean Government CONICYT Fellowships (2006 to 2010). After his doctoral training, he performed postdoctoral studies at the Albert Einstein College of Medicine in New York, NY (2012 to 2016), supported by the prestigious Pew Latin American Fellow in Biomedical Sciences. His main research interest is to explore novel ways to modulate the immune responses based on the study of the properties of NKT cells, their ligands, and their impact on T cells and B cells. He has been working in immune modulation for more than 15 years in order to find novel mechanisms that can be translated into human therapies.
Alexis M. Kalergis, PhD, is a Full Professor at the Schools of Biological Sciences and Medicine of the Pontificia Universidad Católica de Chile and Visiting Faculty at The Albert Einstein College of Medicine, New York, NY, the University of Nantes, France, and the University of Iowa, where he recently held a Helen C. Levitt Visiting Professorship. He is a Biochemistry graduate from Pontificia Universidad Católica of Chile and obtained his PhD in microbiology and immunology from the Albert Einstein College of Medicine in New York, NY. His graduate work was awarded the Julius Marmur Award for the best thesis. Then, he worked as a postdoctoral trainee at the Albert Einstein College of Medicine and Rockefeller University, supported by a Helen Hay Whitney Fellowship. He has lectured as an invited speaker in 250 national and international conferences, published more than 240 articles in leading journals, and has more than 30 patent applications. He is a member of scientific societies, including the American Society of Immunology, the Federation of Clinical Immunology Societies, and the Chilean Societies for Biology, Cell Biology, Biochemistry-Molecular Biology and Immunology. Back in Chile, he was given in 2004 the national award to the most outstanding young scientist by the Biology Society of Chile and selected as one of the fifty Chilean young leaders in 2005. He was included as a member of the Frontiers of Science Program of the Chilean Academy of Sciences. He has been awarded several important national and international research grants leading to the establishment of a productive program on translational immunology. He has been Director of the Millennium Nucleus and Institute on Immunology and Immunotherapy, a Chilean Excellence Center that was appointed as a Center of Excellence by the Federation of Clinical of Immunology Societies, in which he serves as a Board of Director member. Furthermore, he was the founder of a Consortium Grant on Biomedicine that promotes the technological transfer of basic biomedical knowledge to therapeutic tools. He has invested significant efforts in training young scientists and was appointed as a member of the Presidential Science Committee and the Senate Committee for Science. Furthermore, he was recently nominated as Scientific Liaison ICGEB and subsequently a member of the Council of Scientific Advisors of the ICGEB (a United Nations Organization). He was awarded the Gold Medal by the World Intellectual Property Organization and the National Innovation Award in Chile. He was also recently incorporated to the Chilean Academy of Sciences.
REFERENCES
- 1.Mak TW, Saunders ME, Jett BD. 2014. Primer to the immune response, 2nd ed. Elsevier, Burlington, MA. [Google Scholar]
- 2.Lanier LL. 2013. Shades of grey—the blurring view of innate and adaptive immunity. Nat Rev Immunol 13:73–74. doi: 10.1038/nri3389. [DOI] [PubMed] [Google Scholar]
- 3.Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124:783–801. doi: 10.1016/j.cell.2006.02.015. [DOI] [PubMed] [Google Scholar]
- 4.Fan X, Rudensky AY. 2016. Hallmarks of tissue-resident lymphocytes. Cell 164:1198–1211. doi: 10.1016/j.cell.2016.02.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bennett MS, Round JL, Leung DT. 2015. Innate-like lymphocytes in intestinal infections. Curr Opin Infect Dis 28:457–463. doi: 10.1097/QCO.0000000000000189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bix M, Locksley RM. 1995. Natural T cells. Cells that co-express NKRP-1 and TCR. J Immunol 155:1020–1022. [PubMed] [Google Scholar]
- 7.Bendelac A. 1995. Mouse NK1+ T cells. Curr Opin Immunol 7:367–374. doi: 10.1016/0952-7915(95)80112-x. [DOI] [PubMed] [Google Scholar]
- 8.MacDonald HR. 1995. NK1.1+ T cell receptor-alpha/beta+ cells: new clues to their origin, specificity, and function. J Exp Med 182:633–638. doi: 10.1084/jem.182.3.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Berzins SP, Ritchie DS. 2014. Natural killer T cells: drivers or passengers in preventing human disease? Nat Rev Immunol 14:640–646. doi: 10.1038/nri3725. [DOI] [PubMed] [Google Scholar]
- 10.Crosby CM, Kronenberg M. 2018. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol 18:559–574. doi: 10.1038/s41577-018-0034-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bendelac A, Savage PB, Teyton L. 2007. The biology of NKT cells. Annu Rev Immunol 25:297–336. doi: 10.1146/annurev.immunol.25.022106.141711. [DOI] [PubMed] [Google Scholar]
- 12.Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. 2004. NKT cells: what’s in a name? Nat Rev Immunol 4:231–237. doi: 10.1038/nri1309. [DOI] [PubMed] [Google Scholar]
- 13.Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V, Zajonc DM. 2012. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol 13:851–856. doi: 10.1038/ni.2371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Singh AK, Tripathi P, Cardell SL. 2018. Type II NKT cells: an elusive population with immunoregulatory properties. Front Immunol 9:1969. doi: 10.3389/fimmu.2018.01969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Dhodapkar MV, Kumar V. 2017. Type II NKT cells and their emerging role in health and disease. J Immunol 198:1015–1021. doi: 10.4049/jimmunol.1601399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Marrero I, Ware R, Kumar V. 2015. Type II NKT cells in inflammation, autoimmunity, microbial immunity, and cancer. Front Immunol 6:316. doi: 10.3389/fimmu.2015.00316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Calabi F, Milstein C. 2000. The molecular biology of CD1. Semin Immunol 12:503–509. doi: 10.1006/smim.2000.0271. [DOI] [PubMed] [Google Scholar]
- 18.Bricard G, Venkataswamy MM, Yu KOA, Im JS, Ndonye RM, Howell AR, Veerapen N, Illarionov PA, Besra GS, Li Q, Chang Y-T, Porcelli SA. 2010. α-Galactosylceramide analogs with weak agonist activity for human iNKT cells define new candidate anti-inflammatory agents. PLoS One 5:e14374. doi: 10.1371/journal.pone.0014374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Natori T, Koezuka Y, Higa T. 1993. Agelasphins, novel α-galactosylceramides from the marine sponge Agelas mauritianus. Tetrahedron Lett 34:5591–5592. doi: 10.1016/S0040-4039(00)73889-5. [DOI] [Google Scholar]
- 20.Wun KS, Ross F, Patel O, Besra GS, Porcelli SA, Richardson SK, Keshipeddy S, Howell AR, Godfrey DI, Rossjohn J. 2012. Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. J Biol Chem 287:39139–39148. doi: 10.1074/jbc.M112.412320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Mallevaey T, Clarke AJ, Scott-Browne JP, Young MH, Roisman LC, Pellicci DG, Patel O, Vivian JP, Matsuda JL, McCluskey J, Godfrey DI, Marrack P, Rossjohn J, Gapin L. 2011. A molecular basis for NKT cell recognition of CD1d-self-antigen. Immunity 34:315–326. doi: 10.1016/j.immuni.2011.01.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Aoyagi T, Yamamoto N, Hatta M, Tanno D, Miyazato A, Ishii K, Suzuki K, Nakayama T, Taniguchi M, Kunishima H, Hirakata Y, Kaku M, Kawakami K. 2011. Activation of pulmonary invariant NKT cells leads to exacerbation of acute lung injury caused by LPS through local production of IFN-γ and TNF-α by Gr-1+ monocytes. Int Immunol 23:97–108. doi: 10.1093/intimm/dxq460. [DOI] [PubMed] [Google Scholar]
- 23.Slauenwhite D, Johnston B. 2015. Regulation of NKT cell localization in homeostasis and infection. Front Immunol 6:255. doi: 10.3389/fimmu.2015.00255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Eberl G, Lees R, Smiley ST, Taniguchi M, Grusby MJ, MacDonald HR. 1999. Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. J Immunol 162:6410–6419. [PubMed] [Google Scholar]
- 25.Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A. 2000. In vivo identification of glycolipid antigen-specific T cells using fluorescent Cd1d tetramers. J Exp Med 191:1895–1904. doi: 10.1084/jem.191.11.1895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Laloux V, Beaudoin L, Ronet C, Lehuen A. 2002. Phenotypic and functional differences between NKT cells colonizing splanchnic and peripheral lymph nodes. J Immunol 168:3251–3258. doi: 10.4049/jimmunol.168.7.3251. [DOI] [PubMed] [Google Scholar]
- 27.Hobbs JA, Cho S, Roberts TJ, Sriram V, Zhang J, Xu M, Brutkiewicz RR. 2001. Selective loss of natural killer T cells by apoptosis following infection with lymphocytic choriomeningitis virus. J Virol 75:10746–10754. doi: 10.1128/JVI.75.22.10746-10754.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lin Y, Roberts TJ, Wang C-R, Cho S, Brutkiewicz R. 2005. Long-term loss of canonical NKT cells following an acute virus infection. Eur J Immunol 35:879–889. doi: 10.1002/eji.200425495. [DOI] [PubMed] [Google Scholar]
- 29.Lin Y, Roberts TJ, Spence PM, Brutkiewicz RR. 2005. Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection. J Leukoc Biol 77:151–158. doi: 10.1189/jlb.0704399. [DOI] [PubMed] [Google Scholar]
- 30.Brutkiewicz RR, Yunes-Medina L, Liu J. 2018. Immune evasion of the CD1d/NKT cell axis. Curr Opin Immunol 52:87–92. doi: 10.1016/j.coi.2018.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Reilly EC, Wands JR, Brossay L. 2010. Cytokine dependent and independent iNKT cell activation. Cytokine 51:227–231. doi: 10.1016/j.cyto.2010.04.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nishimura T. 1999. The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med 189:1121–1128. doi: 10.1084/jem.189.7.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Albarran B, Goncalves L, Salmen S, Borges L, Fields H, Soyano A, Montes H, Berrueta L. 2005. Profiles of NK, NKT cell activation and cytokine production following vaccination against hepatitis B. APMIS 113:526–535. doi: 10.1111/j.1600-0463.2005.apm_191.x. [DOI] [PubMed] [Google Scholar]
- 34.Wilson MT, Johansson C, Olivares-Villagomez D, Singh AK, Stanic AK, Wang C-R, Joyce S, Wick MJ, Van Kaer L. 2003. The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion. Proc Natl Acad Sci U S A 100:10913–10918. doi: 10.1073/pnas.1833166100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Chang W-S, Kim J-Y, Kim Y-J, Kim Y-S, Lee J-M, Azuma M, Yagita H, Kang C-Y. 2008. Cutting edge: programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol 181:6707–6710. doi: 10.4049/jimmunol.181.10.6707. [DOI] [PubMed] [Google Scholar]
- 36.Crowe NY, Uldrich AP, Kyparissoudis K, Hammond KJL, Hayakawa Y, Sidobre S, Keating R, Kronenberg M, Smyth MJ, Godfrey DI. 2003. Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells. J Immunol 171:4020–4027. doi: 10.4049/jimmunol.171.8.4020. [DOI] [PubMed] [Google Scholar]
- 37.Carnaud C, Lee D, Donnars O, Park SH, Beavis A, Koezuka Y, Bendelac A. 1999. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol 163:4647–4650. [PubMed] [Google Scholar]
- 38.Eberl G, MacDonald HR. 2000. Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells. Eur J Immunol 30:985–992. doi:. [DOI] [PubMed] [Google Scholar]
- 39.Horowitz A, Stegmann KA, Riley EM. 2011. Activation of natural killer cells during microbial infections. Front Immunol 2:88. doi: 10.3389/fimmu.2011.00088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Paulnock D. 1992. Macrophage activation by T cells. Curr Opin Immunol 4:344–349. doi: 10.1016/0952-7915(92)90087-U. [DOI] [PubMed] [Google Scholar]
- 41.Kim JH, Chung DH. 2011. CD1d-restricted IFN-γ-secreting NKT cells promote immune complex-induced acute lung injury by regulating macrophage-inflammatory protein-1α production and activation of macrophages and dendritic cells. J Immunol 186:1432–1441. doi: 10.4049/jimmunol.1003140. [DOI] [PubMed] [Google Scholar]
- 42.Ahn S, Jeong D, Oh SJ, Ahn J, Lee SH, Chung DH. 2017. GM-CSF and IL-4 produced by NKT cells inversely regulate IL-1β production by macrophages. Immunol Lett 182:50–56. doi: 10.1016/j.imlet.2017.01.003. [DOI] [PubMed] [Google Scholar]
- 43.Kim JH, Oh SJ, Ahn S, Chung DH. 2014. IFN-γ-producing NKT cells exacerbate sepsis by enhancing C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils. Eur J Immunol 44:2025–2035. doi: 10.1002/eji.201343937. [DOI] [PubMed] [Google Scholar]
- 44.Huang E, Liu R, Lu Z, Liu J, Liu X, Zhang D, Chu Y. 2016. NKT cells mediate the recruitment of neutrophils by stimulating epithelial chemokine secretion during colitis. Biochem Biophys Res Commun 474:252–258. doi: 10.1016/j.bbrc.2016.04.024. [DOI] [PubMed] [Google Scholar]
- 45.Tanno H, Kawakami K, Kanno E, Suzuki A, Takagi N, Yamamoto H, Ishii K, Imai Y, Maruyama R, Tachi M. 2017. Invariant NKT cells promote skin wound healing by preventing a prolonged neutrophilic inflammatory response. Wound Repair Regen 25:805–815. doi: 10.1111/wrr.12588. [DOI] [PubMed] [Google Scholar]
- 46.Gonzalez Roldan N, Orinska Z, Ewers H, Bulfone-Paus S. 2016. CD252 regulates mast cell mediated, CD1d-restricted NKT-cell activation in mice. Eur J Immunol 46:432–439. doi: 10.1002/eji.201545879. [DOI] [PubMed] [Google Scholar]
- 47.Leite-de-Moraes MC, Diem S, Michel M-L, Ohtsu H, Thurmond RL, Schneider E, Dy M. 2009. Cutting edge: histamine receptor H4 activation positively regulates in vivo IL-4 and IFN-γ production by invariant NKT cells. J Immunol 182:1233–1236. doi: 10.4049/jimmunol.182.3.1233. [DOI] [PubMed] [Google Scholar]
- 48.Van Kaer L, Parekh VV, Wu L. 2015. The response of CD1d-restricted invariant NKT cells to microbial pathogens and their products. Front Immunol 6:226. doi: 10.3389/fimmu.2015.00226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Diao H, Kon S, Iwabuchi K, Kimura C, Morimoto J, Ito D, Segawa T, Maeda M, Hamuro J, Nakayama T, Taniguchi M, Yagita H, Van Kaer L, Onóe K, Denhardt D, Rittling S, Uede T. 2004. Osteopontin as a mediator of NKT cell function in T cell-mediated liver diseases. Immunity 21:539–550. doi: 10.1016/j.immuni.2004.08.012. [DOI] [PubMed] [Google Scholar]
- 50.Kaiko GE, Horvat JC, Beagley KW, Hansbro PM. 2008. Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology 123:326–338. doi: 10.1111/j.1365-2567.2007.02719.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Nishimura T, Kitamura H, Iwakabe K, Yahata T, Ohta A, Sato M, Takeda K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nakui M, Sekimoto M, Koda T. 2000. The interface between innate and acquired immunity: glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes. Int Immunol 12:987–994. doi: 10.1093/intimm/12.7.987. [DOI] [PubMed] [Google Scholar]
- 52.Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. 2013. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 14:1146–1154. doi: 10.1038/ni.2731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Matsuda JL, Mallevaey T, Scott-Browne J, Gapin L. 2008. CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system. Curr Opin Immunol 20:358–368. doi: 10.1016/j.coi.2008.03.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Chang PP, Barral P, Fitch J, Pratama A, Ma CS, Kallies A, Hogan JJ, Cerundolo V, Tangye SG, Bittman R, Nutt SL, Brink R, Godfrey DI, Batista FD, Vinuesa CG. 2011. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol 13:35–43. doi: 10.1038/ni.2166. [DOI] [PubMed] [Google Scholar]
- 55.Barral P, Eckl-Dorna J, Harwood NE, De Santo C, Salio M, Illarionov P, Besra GS, Cerundolo V, Batista FD. 2008. B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc Natl Acad Sci U S A 105:8345–8350. doi: 10.1073/pnas.0802968105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Galli G, Nuti S, Tavarini S, Galli-Stampino L, De Lalla C, Casorati G, Dellabona P, Abrignani S. 2003. CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J Exp Med 197:1051–1057. doi: 10.1084/jem.20021616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Kitamura H, Ohta A, Sekimoto M, Sato M, Iwakabe K, Nakui M, Yahata T, Meng H, Koda T, Nishimura SI, Kawano T, Taniguchi M, Nishimura T. 2000. α-Galactosylceramide induces early B-cell activation through IL-4 production by NKT cells. Cell Immunol 199:37–42. doi: 10.1006/cimm.1999.1602. [DOI] [PubMed] [Google Scholar]
- 58.Galli G, Pittoni P, Tonti E, Malzone C, Uematsu Y, Tortoli M, Maione D, Volpini G, Finco O, Nuti S, Tavarini S, Dellabona P, Rappuoli R, Casorati G, Abrignani S. 2007. Invariant NKT cells sustain specific B cell responses and memory. Proc Natl Acad Sci U S A 104:3984–3989. doi: 10.1073/pnas.0700191104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Leadbetter EA, Brigl M, Illarionov P, Cohen N, Luteran MC, Pillai S, Besra GS, Brenner MB. 2008. NK T cells provide lipid antigen-specific cognate help for B cells. Proc Natl Acad Sci U S A 105:8339–8344. doi: 10.1073/pnas.0801375105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Gaya M, Barral P, Burbage M, Aggarwal S, Montaner B, Warren Navia A, Aid M, Tsui C, Maldonado P, Nair U, Ghneim K, Fallon PG, Sekaly RP, Barouch DH, Shalek AK, Bruckbauer A, Strid J, Batista FD. 2018. Initiation of antiviral B cell immunity relies on innate signals from spatially positioned NKT cells. Cell 172:517.e20–533.e20. doi: 10.1016/j.cell.2017.11.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Balato A, Unutmaz D, Gaspari AA. 2009. Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. J Invest Dermatol 129:1628–1642. doi: 10.1038/jid.2009.30. [DOI] [PubMed] [Google Scholar]
- 62.Li X, Fujio M, Imamura M, Wu D, Vasan S, Wong C-H, Ho DD, Tsuji M. 2010. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc Natl Acad Sci U S A 107:13010–13015. doi: 10.1073/pnas.1006662107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Carreño LJ, Saavedra-Ávila NA, Porcelli SA. 2016. Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents. Clin Transl Immunology 5:e69. doi: 10.1038/cti.2016.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Padte NN, Li X, Tsuji M, Vasan S. 2011. Clinical development of a novel CD1d-binding NKT cell ligand as a vaccine adjuvant. Clin Immunol 140:142–151. doi: 10.1016/j.clim.2010.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Miyamoto K, Miyake S, Yamamura T. 2001. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413:531–534. doi: 10.1038/35097097. [DOI] [PubMed] [Google Scholar]
- 66.Yu KOA, Im JS, Molano A, Dutronc Y, Illarionov PA, Forestier C, Fujiwara N, Arias I, Miyake S, Yamamura T, Chang Y-T, Besra GS, Porcelli SA. 2005. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of α-galactosylceramides. Proc Natl Acad Sci U S A 102:3383–3388. doi: 10.1073/pnas.0407488102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Wieland Brown LC, Penaranda C, Kashyap PC, Williams BB, Clardy J, Kronenberg M, Sonnenburg JL, Comstock LE, Bluestone JA, Fischbach MA. 2013. Production of α-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol 11:e1001610. doi: 10.1371/journal.pbio.1001610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.An D, Oh SF, Olszak T, Neves JF, Avci FY, Erturk-Hasdemir D, Lu X, Zeissig S, Blumberg RS, Kasper DL. 2014. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156:123–133. doi: 10.1016/j.cell.2013.11.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Uldrich AP, Crowe NY, Kyparissoudis K, Pellicci DG, Zhan Y, Lew AM, Bouillet P, Strasser A, Smyth MJ, Godfrey DI. 2005. NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-Dependent Contraction, And Hyporesponsiveness To Further Antigenic Challenge. J Immunol 175:3092–3101. doi: 10.4049/jimmunol.175.5.3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Trottein F, Paget C. 2018. Natural killer T cells and mucosal-associated invariant T cells in lung infections. Front Immunol 9:1750. doi: 10.3389/fimmu.2018.01750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Bedel R, Matsuda JL, Brigl M, White J, Kappler J, Marrack P, Gapin L. 2012. Lower TCR repertoire diversity in Traj18-deficient mice. Nat Immunol 13:705–706. doi: 10.1038/ni.2347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Engholm DH, Kilian M, Goodsell DS, Andersen ES, Kjærgaard RS. 2017. A visual review of the human pathogen Streptococcus pneumoniae. FEMS Microbiol Rev 41:854–879. doi: 10.1093/femsre/fux037. [DOI] [PubMed] [Google Scholar]
- 73.Kawakami K, Yamamoto N, Kinjo Y, Miyagi K, Nakasone C, Uezu K, Kinjo T, Nakayama T, Taniguchi M, Saito A. 2003. Critical role of Vα14+ natural killer T cells in the innate phase of host protection against Streptococcus pneumoniae infection. Eur J Immunol 33:3322–3330. doi: 10.1002/eji.200324254. [DOI] [PubMed] [Google Scholar]
- 74.Nakamatsu M, Yamamoto N, Hatta M, Nakasone C, Kinjo T, Miyagi K, Uezu K, Nakamura K, Nakayama T, Taniguchi M, Iwakura Y, Kaku M, Fujita J, Kawakami K. 2007. Role of interferon-γ in Vα14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs. Microbes Infect 9:364–374. doi: 10.1016/j.micinf.2006.12.003. [DOI] [PubMed] [Google Scholar]
- 75.Kinjo Y, Illarionov P, Vela JL, Pei B, Girardi E, Li X, Li Y, Imamura M, Kaneko Y, Okawara A, Miyazaki Y, Gómez-Velasco A, Rogers P, Dahesh S, Uchiyama S, Khurana A, Kawahara K, Yesilkaya H, Andrew PW, Wong C-H, Kawakami K, Nizet V, Besra GS, Tsuji M, Zajonc DM, Kronenberg M. 2011. Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat Immunol 12:966–974. doi: 10.1038/ni.2096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Ivanov S, Fontaine J, Paget C, MacHo Fernandez E, Van Maele L, Renneson J, Maillet I, Wolf NM, Rial A, Léger H, Ryffel B, Frisch B, Chabalgoity JA, Sirard JC, Benecke A, Faveeuw C, Trottein F. 2012. Key role for respiratory CD103+ dendritic cells, IFN-, and IL-17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide. J Infect Dis 206:723–734. doi: 10.1093/infdis/jis413. [DOI] [PubMed] [Google Scholar]
- 77.Thorburn AN, Foster PS, Gibson PG, Hansbro PM. 2012. Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells. J Immunol 188:4611–4620. doi: 10.4049/jimmunol.1101299. [DOI] [PubMed] [Google Scholar]
- 78.Houben RMGJ, Dodd PJ. 2016. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 13:e1002152. doi: 10.1371/journal.pmed.1002152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Kawakami K, Kinjo Y, Uezu K, Yara S, Miyagi K, Koguchi Y, Nakayama T, Taniguchi M, Saito A. 2002. Minimal contribution of Valpha14 natural killer T cells to Th1 response and host resistance against mycobacterial infection in mice. Microbiol Immunol 46:207–210. doi: 10.1111/j.1348-0421.2002.tb02687.x. [DOI] [PubMed] [Google Scholar]
- 80.Li Z, Yang B, Zhang Y, Ma J, Chen X, Lao S, Li B, Wu C. 2014. Mycobacterium tuberculosis-specific memory NKT cells in patients with tuberculous pleurisy. J Clin Immunol 34:979–990. doi: 10.1007/s10875-014-0090-8. [DOI] [PubMed] [Google Scholar]
- 81.Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. 1993. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 178:2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Rothchild AC, Jayaraman P, Nunes-Alves C, Behar SM. 2014. iNKT cell production of GM-CSF controls Mycobacterium tuberculosis. PLoS Pathog 10:e1003805. doi: 10.1371/journal.ppat.1003805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Wu C, Li Z, Fu X, Yu S, Lao S, Yang B. 2015. Antigen-specific human NKT cells from tuberculosis patients produce IL-21 to help B cells for the production of immunoglobulins. Oncotarget 6:28633–28645. doi: 10.18632/oncotarget.5764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Fischer K, Scotet E, Niemeyer M, Koebernick H, Zerrahn J, Maillet S, Hurwitz R, Kursar M, Bonneville M, Kaufmann SHE, Schaible UE. 2004. Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells. Proc Natl Acad Sci U S A 101:10685–10690. doi: 10.1073/pnas.0403787101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Sada-Ovalle I, Sköld M, Tian T, Besra GS, Behar SM. 2010. α-Galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 182:841–847. doi: 10.1164/rccm.200912-1921OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Snyder‐Cappione JE, Nixon DF, Loo CP, Chapman JM, Meiklejohn DA, Melo FF, Costa PR, Sandberg JK, Rodrigues DS, Kallas EG. 2007. Individuals with pulmonary tuberculosis have lower levels of circulating CD1d‐restricted NKT cells. J Infect Dis 195:1361–1364. doi: 10.1086/513567. [DOI] [PubMed] [Google Scholar]
- 87.Apostolou I, Takahama Y, Belmant C, Kawano T, Huerre M, Marchal G, Cui J, Taniguchi M, Nakauchi H, Fournie J-J, Kourilsky P, Gachelin G. 1999. Murine natural killer T cells contribute to the granulomatous reaction caused by mycobacterial cell walls. Proc Natl Acad Sci U S A 96:5141–5146. doi: 10.1073/pnas.96.9.5141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Sada-Ovalle I, Chiba A, Gonzales A, Brenner MB, Behar SM. 2008. Innate invariant NKT Cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-γ, and kill intracellular bacteria. PLoS Pathog 4:e1000239. doi: 10.1371/journal.ppat.1000239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Thompson WW, Comanor L, Shay DK. 2006. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis 194:S82–S91. doi: 10.1086/507558. [DOI] [PubMed] [Google Scholar]
- 90.Ho L-P, Denney L, Luhn K, Teoh D, Clelland C, McMichael AJ. 2008. Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection. Eur J Immunol 38:1913–1922. doi: 10.1002/eji.200738017. [DOI] [PubMed] [Google Scholar]
- 91.De Santo C, Salio M, Masri SH, Lee LYH, Dong T, Speak AO, Porubsky S, Booth S, Veerapen N, Besra GS, Gröne HJ, Platt FM, Zambon M, Cerundolo V. 2008. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest 118:4036–4048. doi: 10.1172/JCI36264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Maazi H, Singh AK, Speak AO, Lombardi V, Lam J, Khoo B, Inn KS, Sharpe AH, Jung JU, Akbari O. 2013. Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection. PLoS One 8:e59599. doi: 10.1371/journal.pone.0059599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Artiaga BL, Yang G, Hutchinson TE, Loeb JC, Richt JA, Lednicky JA, Salek-Ardakani S, Driver JP. 2016. Rapid control of pandemic H1N1 influenza by targeting NKT cells. Sci Rep 6:37999. doi: 10.1038/srep37999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Guillonneau C, Mintern JD, Hubert F-X, Hurt AC, Besra GS, Porcelli S, Barr IG, Doherty PC, Godfrey DI, Turner SJ. 2009. Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity. Proc Natl Acad Sci U S A 106:3330–3335. doi: 10.1073/pnas.0813309106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Yang G, Richt J, Driver J. 2017. Harnessing invariant NKT cells to improve influenza vaccines: a pig perspective. Int J Mol Sci 19:68. doi: 10.3390/ijms19010068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Chen J, Varma A, Diaz MR, Litvintseva AP, Wollenberg KK, Kwon-Chung KJ. 2008. Cryptococcus neoformans strains and infection in apparently immunocompetent patients, China. Emerg Infect Dis 14:755–762. doi: 10.3201/eid1405.071312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Lui G, Lee N, Ip M, Choi KW, Tso YK, Lam E, Chau S, Lai R, Cockram CS. 2006. Cryptococcosis in apparently immunocompetent patients. QJM 99:143–151. doi: 10.1093/qjmed/hcl014. [DOI] [PubMed] [Google Scholar]
- 98.Kawakami K, Kinjo Y, Yara S, Koguchi Y, Uezu K, Nakayama T, Taniguchi M, Saito A. 2001. Activation of Vα14+ natural killer T cells by α-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect Immun 69:213–220. doi: 10.1128/IAI.69.1.213-220.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Coelho C, Bocca AL, Casadevall A. 2014. The intracellular life of Cryptococcus neoformans. Annu Rev Pathol 9:219–238. doi: 10.1146/annurev-pathol-012513-104653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Kawakami K, Kinjo Y, Uezu K, Yara S, Miyagi K, Koguchi Y, Nakayama T, Taniguchi M, Saito A. 2001. Monocyte chemoattractant protein-1-dependent increase of Vα14 NKT cells in lungs and their roles in Th1 response and host defense in cryptococcal infection. J Immunol 167:6525–6532. doi: 10.4049/jimmunol.167.11.6525. [DOI] [PubMed] [Google Scholar]
- 101.Blackstock R, Murphy JW. 2004. Age-related resistance of C57BL/6 mice to Cryptococcus neoformans is dependent on maturation of NKT cells. Infect Immun 72:5175–5180. doi: 10.1128/IAI.72.9.5175-5180.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Nichols KL, Bauman SK, Schafer FB, Murphy JW. 2002. Differences in components at delayed-type hypersensitivity reaction sites in mice immunized with either a protective or a nonprotective immunogen of Cryptococcus neoformans. Infect Immun 70:591–600. doi: 10.1128/iai.70.2.591-600.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Dickgreber N, Farrand KJ, van Panhuys N, Knight DA, McKee SJ, Chong ML, Miranda-Hernandez S, Baxter AG, Locksley RM, Le Gros G, Hermans IF. 2012. Immature murine NKT cells pass through a stage of developmentally programmed innate IL-4 secretion. J Leukoc Biol 92:999–1009. doi: 10.1189/jlb.0512242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Gadue P, Stein PL. 2002. NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. J Immunol 169:2397–2406. doi: 10.4049/jimmunol.169.5.2397. [DOI] [PubMed] [Google Scholar]
- 105.Pellicci DG, Hammond KJL, Uldrich AP, Baxter AG, Smyth MJ, Godfrey DI. 2002. A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1−CD4+ CD1d-dependent precursor stage. J Exp Med 195:835–844. doi: 10.1084/jem.20011544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Das R, Sant'Angelo DB, Nichols KE. 2010. Transcriptional control of invariant NKT cell development. Immunol Rev 238:195–215. doi: 10.1111/j.1600-065X.2010.00962.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Kadowaki N, Antonenko S, Ho S, Rissoan M-C, Soumelis V, Porcelli SA, Lanier LL, Liu Y-J. 2001. Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells. J Exp Med 193:1221–1226. doi: 10.1084/jem.193.10.1221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Ribeiro VSG, Hasan M, Wilson A, Boucontet L, Pereira P, Lesjean-Pottier S, Satoh-Takayama N, Di Santo JP, Vosshenrich CAJ. 2010. Cutting edge: thymic NK cells develop independently from T cell precursors. J Immunol 185:4993–4997. doi: 10.4049/jimmunol.1002273. [DOI] [PubMed] [Google Scholar]
- 109.Vosshenrich CAJ, García-Ojeda ME, Samson-Villéger SI, Pasqualetto V, Enault L, Goff OR-L, Corcuff E, Guy-Grand D, Rocha B, Cumano A, Rogge L, Ezine S, Di Santo JP. 2006. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 7:1217–1224. doi: 10.1038/ni1395. [DOI] [PubMed] [Google Scholar]
- 110.Mittrücker H-W, Kaufmann SHE. 2000. Immune response to infection with Salmonella Typhimurium in mice. J Leukoc Biol 67:457–463. doi: 10.1002/jlb.67.4.457. [DOI] [PubMed] [Google Scholar]
- 111.McClelland M, Sanderson KE, Spieth J, Clifton SW, Latreille P, Courtney L, Porwollik S, Ali J, Dante M, Du F, Hou S, Layman D, Leonard S, Nguyen C, Scott K, Holmes A, Grewal N, Mulvaney E, Ryan E, Sun H, Florea L, Miller W, Stoneking T, Nhan M, Waterston R, Wilson RK. 2001. Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. Nature 413:852–856. doi: 10.1038/35101614. [DOI] [PubMed] [Google Scholar]
- 112.Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB. 2003. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4:1230–1237. doi: 10.1038/ni1002. [DOI] [PubMed] [Google Scholar]
- 113.Mattner J, DeBord KL, Ismail N, Goff RD, Cantu C, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A. 2005. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529. doi: 10.1038/nature03408. [DOI] [PubMed] [Google Scholar]
- 114.Holzapfel KL, Tyznik AJ, Kronenberg M, Hogquist KA. 2014. Antigen-dependent versus -independent activation of invariant NKT cells during infection. J Immunol 192:5490–5498. doi: 10.4049/jimmunol.1400722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Amajoud N, Leclercq A, Soriano JM, Bracq-Dieye H, El Maadoudi M, Senhaji NS, Kounnoun A, Moura A, Lecuit M, Abrini J. 2018. Prevalence of Listeria spp. and characterization of Listeria monocytogenes isolated from food products in Tetouan, Morocco. Food Control 84:436–441. doi: 10.1016/j.foodcont.2017.08.023. [DOI] [Google Scholar]
- 116.Ranson T, Bregenholt S, Lehuen A, Gaillot O, Leite-de-Moraes MC, Herbelin A, Berche P, Di Santo JP. 2005. Invariant V alpha 14+ NKT cells participate in the early response to enteric Listeria monocytogenes infection. J Immunol 175:1137–1144. doi: 10.4049/jimmunol.175.2.1137. [DOI] [PubMed] [Google Scholar]
- 117.Chen Z, Zhu S, Wang L, Xie D, Zhang H, Li X, Zheng X, Du Z, Li J, Bai L. 2018. Memory follicular helper invariant NKT cells recognize lipid antigens on memory B cells and elicit antibody recall responses. J Immunol 200:3117–3127. doi: 10.4049/jimmunol.1701026. [DOI] [PubMed] [Google Scholar]
- 118.Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M. 1993. Immune response in mice that lack the interferon-gamma receptor. Science 259:1742–1745. doi: 10.1126/science.8456301. [DOI] [PubMed] [Google Scholar]
- 119.Harty JT, Bevant MJ. 1995. Specific immunity to listeria monocytogenes in the absence of IFNγ. Immunity 3:109–117. doi: 10.1016/1074-7613(95)90163-9. [DOI] [PubMed] [Google Scholar]
- 120.Szalay G, Ladel CH, Blum C, Brossay L, Kronenberg M, Kaufmann SH. 1999. Cutting edge: anti-CD1 monoclonal antibody treatment reverses the production patterns of TGF-beta 2 and Th1 cytokines and ameliorates listeriosis in mice. J Immunol 162:6955–6958. [PubMed] [Google Scholar]
- 121.Doisne J-M, Bartholin L, Yan K-P, Garcia CN, Duarte N, Le Luduec J-B, Vincent D, Cyprian F, Horvat B, Martel S, Rimokh R, Losson R, Benlagha K, Marie JC. 2009. iNKT cell development is orchestrated by different branches of TGF-β signaling. J Exp Med 206:1365–1378. doi: 10.1084/jem.20090127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.Havenar-Daughton C, Li S, Benlagha K, Marie JC. 2012. Development and function of murine RORγt+ iNKT cells are under TGF-β signaling control. Blood 119:3486–3494. doi: 10.1182/blood-2012-01-401604. [DOI] [PubMed] [Google Scholar]
- 123.Denney L, Branchett W, Gregory LG, Oliver RA, Lloyd CM. 2018. Epithelial-derived TGF-β1 acts as a pro-viral factor in the lung during influenza A infection. Mucosal Immunol 11:523–535. doi: 10.1038/mi.2017.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Hirsch CS, Yoneda T, Averill L, Ellner JJ, Toossi Z. 1994. Enhancement of intracellular growth of Mycobacterium tuberculosis in human monocytes by transforming growth factor- l. J Infect Dis 170:1229–1237. doi: 10.1093/infdis/170.5.1229. [DOI] [PubMed] [Google Scholar]
- 125.Igietseme JU, Partin J, George Z, Omosun Y, Goldstein J, Joseph K, Ellerson D, Eko FO, Pohl J, Bandea C, Black CM. 2020. Epidermal growth factor receptor and transforming growth factor β signaling pathways cooperate to mediate Chlamydia pathogenesis. Infect Immun 88:e00819-19. doi: 10.1128/IAI.00819-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Nakane A, Asano M, Sasaki S, Nishikawa S, Miura T, Kohanawa M, Minagawa T. 1996. Transforming growth factor beta is protective in host resistance against Listeria monocytogenes infection in mice. Infect Immun 64:3901–3904. doi: 10.1128/IAI.64.9.3901-3904.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Penna G, Sozzani S, Adorini L. 2001. Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells. J Immunol 167:1862–1866. doi: 10.4049/jimmunol.167.4.1862. [DOI] [PubMed] [Google Scholar]
- 128.Han Y, Jiang Z, Chen Z, Gu Y, Liu Y, Zhang X, Cao X. 2015. Pathogen-expanded CD11b+ invariant NKT cells feedback inhibit T cell proliferation via membrane-bound TGF-β1. J Autoimmun 58:21–35. doi: 10.1016/j.jaut.2014.12.006. [DOI] [PubMed] [Google Scholar]
- 129.Emoto M, Yoshida T, Fukuda T, Kawamura I, Mitsuyama M, Kita E, Hurwitz R, Kaufmann SHE, Emoto Y. 2010. α-Galactosylceramide promotes killing of Listeria monocytogenes within the macrophage phagosome through invariant NKT-cell activation. Infect Immun 78:2667–2676. doi: 10.1128/IAI.01441-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar I, Abu-Raddad LJ, Assadi R, Bhala N, Cowie B, Forouzanfour MH, Groeger J, Hanafiah KM, Jacobsen KH, James SL, MacLachlan J, Malekzadeh R, Martin NK, Mokdad AHA, Mokdad AHA, Murray CJL, Plass D, Rana S, Rein DB, Richardus JH, Sanabria J, Saylan M, Shahraz S, So S, Vlassov VV, Weiderpass E, Wiersma ST, Younis M, Yu C, El Sayed Zaki M, Cooke GS. 2016. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet 388:1081–1088. doi: 10.1016/S0140-6736(16)30579-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Deressa T, Damtie D, Fonseca K, Gao S, Abate E, Alemu S, Aleka Y, Swain MG, Van Marle G, Coffin CS. 2017. The burden of hepatitis B virus (HBV) infection, genotypes and drug resistance mutations in human immunodeficiency virus-positive patients in Northwest Ethiopia. PLoS One 12:e0190149. doi: 10.1371/journal.pone.0190149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132.Jiang X, Zhang M, Lai Q, Huang X, Li Y, Sun J, Abbott WGH, Ma S, Hou J. 2011. Restored circulating invariant NKT cells are associated with viral control in patients with chronic hepatitis B. PLoS One 6:e28871. doi: 10.1371/journal.pone.0028871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. 2000. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192:921–930. doi: 10.1084/jem.192.7.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Guidotti LG, McClary H, Loudis JM, Chisari FV. 2000. Nitric oxide inhibits hepatitis B virus replication in the livers of transgenic mice. J Exp Med 191:1247–1252. doi: 10.1084/jem.191.7.1247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.McClary H, Koch R, Chisari FV, Guidotti LG. 2000. Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J Virol 74:2255–2264. doi: 10.1128/jvi.74.5.2255-2264.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Wang XF, Lei Y, Chen M, Chen CB, Ren H, Shi TD. 2013. PD-1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication. J Viral Hepat 20:27–39. doi: 10.1111/jvh.12061. [DOI] [PubMed] [Google Scholar]
- 137.Zhu H, Zhang Y, Liu H, Zhang Y, Kang Y, Mao R, Yang F, Zhou D, Zhang J. 2015. Preserved function of circulating invariant natural killer T cells in patients with chronic hepatitis B virus infection. Medicine (Baltimore) 94:e961. doi: 10.1097/MD.0000000000000961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138.Li M, Zhou ZH, Sun XH, Zhang X, Zhu XJ, Jin SG, Jiang Y, Gao YT, Li CZ, Gao YQ. 2016. The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection. Hepatol Int 10:594–601. doi: 10.1007/s12072-015-9650-0. [DOI] [PubMed] [Google Scholar]
- 139.Tan X, Ding Y, Zhu P, Dou R, Liang Z, Yang D, Huang Z, Wang W, Wu X, Weng X. 2018. Elevated hepatic CD1d levels coincide with invariant NKT cell defects in chronic hepatitis B virus infection. J Immunol 200:3530–3538. doi: 10.4049/jimmunol.1701801. [DOI] [PubMed] [Google Scholar]
- 140.Van Der Vliet HJJ, Molling JW, Von Blomberg BME, Kölgen W, Stam AG, De Gruijl TD, Mulder CJ, Janssen HLA, Nishi N, Van Den Eertwegh AJM, Scheper RJ, Van Nieuwkerk CJM. 2005. Circulating Vα24+ Vβ11+ NKT cell numbers and dendritic cell CD1d expression in hepatitis C virus infected patients. Clin Immunol 114:183–189. doi: 10.1016/j.clim.2004.10.001. [DOI] [PubMed] [Google Scholar]
- 141.Lucas M, Gadola S, Meier U, Young NT, Harcourt G, Karadimitris A, Coumi N, Brown D, Dusheiko G, Cerundolo V, Klenerman P. 2003. Frequency and phenotype of circulating V 24/V 11 double-positive natural killer T cells during hepatitis C virus infection. J Virol 77:2251–2257. doi: 10.1128/jvi.77.3.2251-2257.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.WHO, Regional Office for South-East Asia. 2011. Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever. Revised and expanded edition. WHO, Regional Office for South-East Asia, New Delhi, India. [Google Scholar]
- 143.Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. 2016. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis 16:935–941. doi: 10.1016/S1473-3099(16)00146-8. [DOI] [PubMed] [Google Scholar]
- 144.St John AL, Rathore APS, Yap H, Ng M-L, Metcalfe DD, Vasudevan SG, Abraham SN. 2011. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc Natl Acad Sci U S A 108:9190–9195. doi: 10.1073/pnas.1105079108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Yoshida T, Omatsu T, Saito A, Katakai Y, Iwasaki Y, Kurosawa T, Hamano M, Higashino A, Nakamura S, Takasaki T, Yasutomi Y, Kurane I, Akari H. 2013. Dynamics of cellular immune responses in the acute phase of dengue virus infection. Arch Virol 158:1209–1220. doi: 10.1007/s00705-013-1618-6. [DOI] [PubMed] [Google Scholar]
- 146.Matangkasombut P, Chan-In W, Opasawaschai A, Pongchaikul P, Tangthawornchaikul N, Vasanawathana S, Limpitikul W, Malasit P, Duangchinda T, Screaton G, Mongkolsapaya J. 2014. Invariant NKT cell response to dengue virus infection in human. PLoS Negl Trop Dis 8:e2955. doi: 10.1371/journal.pntd.0002955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. 2015. Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells. Antimicrob Agents Chemother 59:4616–4624. doi: 10.1128/AAC.00864-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.Kumar H, Belperron A, Barthold SW, Bockenstedt LK. 2000. Cutting edge: CD1d deficiency impairs murine host defense against the spirochete, Borrelia burgdorferi. J Immunol 165:4797–4801. doi: 10.4049/jimmunol.165.9.4797. [DOI] [PubMed] [Google Scholar]
- 149.Olson CM, Bates TC, Izadi H, Radolf JD, Huber SA, Boyson JE, Anguita J. 2009. Local production of IFN- by invariant NKT cells modulates acute Lyme carditis. J Immunol 182:3728–3734. doi: 10.4049/jimmunol.0804111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Tsuji M. 2006. Glycolipids and phospholipids as natural CD1d-binding NKT cell ligands. Cell Mol Life Sci 63:1889–1898. doi: 10.1007/s00018-006-6073-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Kinjo Y, Tupin E, Wu D, Fujio M, Garcia-Navarro R, Benhnia M-E-I, Zajonc DM, Ben-Menachem G, Ainge GD, Painter GF, Khurana A, Hoebe K, Behar SM, Beutler B, Wilson IA, Tsuji M, Sellati TJ, Wong C-H, Kronenberg M. 2006. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7:978–986. doi: 10.1038/ni1380. [DOI] [PubMed] [Google Scholar]
- 152.Tupin E, Kinjo Y, Kronenberg M. 2007. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5:405–417. doi: 10.1038/nrmicro1657. [DOI] [PubMed] [Google Scholar]
- 153.Wang J, Li Y, Kinjo Y, Mac T-T, Gibson D, Painter GF, Kronenberg M, Zajonc DM. 2010. Lipid binding orientation within CD1d affects recognition of Borrelia burgdorferi antigens by NKT cells. Proc Natl Acad Sci U S A 107:1535–1540. doi: 10.1073/pnas.0909479107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Lyczak JB, Cannon CL, Pier GB. 2000. Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect 2:1051–1060. doi: 10.1016/s1286-4579(00)01259-4. [DOI] [PubMed] [Google Scholar]
- 155.Sadikot RT, Blackwell TS, Christman JW, Prince AS. 2005. Pathogen–host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 171:1209–1223. doi: 10.1164/rccm.200408-1044SO. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Hawkey PM. 2008. The growing burden of antimicrobial resistance. J Antimicrob Chemother 62:i1–i9. doi: 10.1093/jac/dkn241. [DOI] [PubMed] [Google Scholar]
- 157.Hazlett LD, Li Q, Liu J, McClellan S, Du W, Barrett RP. 2007. NKT cells are critical to initiate an inflammatory response after Pseudomonas aeruginosa ocular infection in susceptible mice. J Immunol 179:1138–1146. doi: 10.4049/jimmunol.179.2.1138. [DOI] [PubMed] [Google Scholar]
- 158.Nieuwenhuis EES, Matsumoto T, Exley M, Schleipman RA, Glickman J, Bailey DT, Corazza N, Colgan SP, Onderdonk AB, Blumberg RS. 2002. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat Med 8:588–593. doi: 10.1038/nm0602-588. [DOI] [PubMed] [Google Scholar]
- 159.Kinjo T, Nakamatsu M, Nakasone C, Yamamoto N, Kinjo Y, Miyagi K, Uezu K, Nakamura K, Higa F, Tateyama M, Takeda K, Nakayama T, Taniguchi M, Kaku M, Fujita J, Kawakami K. 2006. NKT cells play a limited role in the neutrophilic inflammatory responses and host defense to pulmonary infection with Pseudomonas aeruginosa. Microbes Infect 8:2679–2685. doi: 10.1016/j.micinf.2006.07.016. [DOI] [PubMed] [Google Scholar]
- 160.Cui J, Li F, Shi Z-L. 2019. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17:181–192. doi: 10.1038/s41579-018-0118-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Greenberg S. 2016. Update on human rhinovirus and coronavirus infections. Semin Respir Crit Care Med 37:555–571. doi: 10.1055/s-0036-1584797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Khan S, Siddique R, Shereen MA, Ali A, Liu J, Bai Q, Bashir N, Xue M. 2020. Emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2: biology and therapeutic options. J Clin Microbiol 58:e00187-20. doi: 10.1128/JCM.00187-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, Subbarao K. 2010. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) Infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol 84:1289–1301. doi: 10.1128/JVI.01281-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Kim D-M, Seo J-W, Kim Y, Park U, Ha N-Y, Park H, Yun NR, Kim DY, Yoon SH, Na YS, Moon DS, Lim S-C, Kim C-M, Jeon K, Kang J-G, Kim Y-S, Cho N-H. 2020. Acute eosinophilic pneumonia associated with elevated NKT cell response in COVID-19 patients. https://www.researchsquare.com/article/rs-23607/v1. [DOI] [PMC free article] [PubMed]
- 165.Afonso CL, Amarasinghe GK, Bányai K, Bào Y, Basler CF, Bavari S, Bejerman N, Blasdell KR, Briand F-XX, Briese T, Bukreyev A, Calisher CH, Chandran K, Chéng J, Clawson AN, Collins PL, Dietzgen RG, Dolnik O, Domier LL, Dürrwald R, Dye JM, Easton AJ, Ebihara H, Farkas SL, Freitas-Astúa J, Formenty P, Fouchier RAMM, Fù Y, Ghedin E, Goodin MM, Hewson R, Horie M, Hyndman TH, Jiāng D, Kitajima EW, Kobinger GP, Kondo H, Kurath G, Lamb RA, Lenardon S, Leroy EM, Li C-XX, Lin X-DD, Liú L, Longdon B, Marton S, Maisner A, Mühlberger E, Netesov SV, Nowotny N, Patterson JL, Payne SL, Paweska JT, et al. 2016. Taxonomy of the order Mononegavirales: update 2016. Arch Virol 161:2351–2360. doi: 10.1007/s00705-016-2880-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166.Gálvez N, Soto J, Kalergis A. 2017. New insights contributing to the development of effective vaccines and therapies to reduce the pathology caused by hRSV. Int J Mol Sci 18:1753. doi: 10.3390/ijms18081753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Ugonna K, Douros K, Bingle CD, Everard ML. 2016. Cytokine responses in primary and secondary respiratory syncytial virus infections. Pediatr Res 79:946–950. doi: 10.1038/pr.2016.29. [DOI] [PubMed] [Google Scholar]
- 168.Andrade CA, Pacheco GA, Gálvez NMS, Soto JA, Bueno SM, Kalergis AM. 2020. Innate immune components that regulate the pathogenesis and resolution of hRSV and hMPV infections. Viruses 12:637. doi: 10.3390/v12060637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169.Johnson TR, Hong S, Van Kaer L, Koezuka Y, Graham BS. 2002. NK T cells contribute to expansion of CD8+ T cells and amplification of antiviral immune responses to respiratory syncytial virus. J Virol 76:4294–4303. doi: 10.1128/jvi.76.9.4294-4303.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 170.Lee SY, Noh Y, Goo JH, Rho S, Kim MJ, Kang C-Y, Song M, Kim J-O. 2017. Natural killer T cell sensitization during neonatal respiratory syncytial virus infection induces eosinophilic lung disease in re-infected adult mice. PLoS One 12:e0176940. doi: 10.1371/journal.pone.0176940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Rey-Jurado E, Bohmwald K, Gálvez NMS, Becerra D, Porcelli SA, Carreño LJ, Kalergis AM. 2020. Contribution of NKT cells to the immune response and pathogenesis triggered by respiratory viruses. Virulence 11:580–593. doi: 10.1080/21505594.2020.1770492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.Céspedes PF, Bueno SM, Ramírez BA, Gomez RS, Riquelme SA, Palavecino CE, Mackern-Oberti JP, Mora JE, Depoil D, Sacristán C, Cammer M, Creneguy A, Nguyen TH, Riedel CA, Dustin ML, Kalergis AM. 2014. Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. Proc Natl Acad Sci U S A 111:E3214–E3223. doi: 10.1073/pnas.1400760111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Soto JA, Gálvez NMS, Benavente FM, Pizarro-Ortega MS, Lay MK, Riedel C, Bueno SM, Gonzalez PA, Kalergis AM. 2018. Human metapneumovirus: mechanisms and molecular targets used by the virus to avoid the immune system. Front Immunol 9:2466. doi: 10.3389/fimmu.2018.02466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174.Céspedes PF, Gonzalez PA, Kalergis AM. 2013. Human metapneumovirus keeps dendritic cells from priming antigen-specific naive T cells. Immunology 139:366–376. doi: 10.1111/imm.12083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Cohen NR, Tatituri RVV, Rivera A, Watts GFM, Kim EY, Chiba A, Fuchs BB, Mylonakis E, Besra GS, Levitz SM, Brigl M, Brenner MB. 2011. Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi. Cell Host Microbe 10:437–450. doi: 10.1016/j.chom.2011.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Nagai H, Guo J, Choi H, Kurup V. 1995. Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis 172:1554–1560. doi: 10.1093/infdis/172.6.1554. [DOI] [PubMed] [Google Scholar]
- 177.Mehrad B, Strieter RM, Standiford TJ. 1999. Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis. J Immunol 162:1633–1640. [PubMed] [Google Scholar]
- 178.Albacker LA, Chaudhary V, Chang Y-JJ, Kim HY, Chuang Y-TT, Pichavant M, DeKruyff RH, Savage PB, Umetsu DT. 2013. Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med 19:1297–1304. doi: 10.1038/nm.3321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Beitzen-Heineke A, Bouzani M, Schmitt AL, Kurzai O, Hünniger K, Einsele H, Loeffler J. 2016. Human invariant natural killer T cells possess immune-modulating functions during Aspergillus infection. Med Mycol 54:169–176. doi: 10.1093/mmy/myv074. [DOI] [PubMed] [Google Scholar]
- 180.Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. 1993. Enhancement of oxidative response and damage caused by human neutrophils to Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 61:1185–1193. doi: 10.1128/IAI.61.4.1185-1193.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Bilenki L, Wang S, Yang J, Fan Y, Joyee AG, Yang X. 2005. NK T cell activation promotes Chlamydia trachomatis infection in vivo. J Immunol 175:3197–3206. doi: 10.4049/jimmunol.175.5.3197. [DOI] [PubMed] [Google Scholar]
- 182.Shimamura M, Yamamura M, Nabeshima T, Kitano N, van den Elzen P, Yesilkaya H, Andrew P, Illarionov P. 2017. Activation of invariant natural killer T cells stimulated with microbial α-mannosyl glycolipids. Sci Rep 7:9703. doi: 10.1038/s41598-017-10309-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 183.Tarumoto N, Kinjo Y, Ueno K, Okawara A, Watarai H, Taniguchi M, Maesaki S, Miyazaki Y. 2012. A limited role of iNKT cells in controlling systemic Candida albicans infections. Jpn J Infect Dis 65:522–526. doi: 10.7883/yoken.65.522. [DOI] [PubMed] [Google Scholar]
- 184.Tarumoto N, Kinjo Y, Kitano N, Sasai D, Ueno K, Okawara A, Izawa Y, Shinozaki M, Watarai H, Taniguchi M, Takeyama H, Maesaki S, Shibuya K, Miyazaki Y. 2014. Exacerbation of invasive Candida albicans infection by commensal bacteria or a glycolipid through IFN-γ produced in part by iNKT cells. J Infect Dis 209:799–810. doi: 10.1093/infdis/jit534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185.Haraguchi N, Kikuchi N, Morishima Y, Matsuyama M, Sakurai H, Shibuya A, Shibuya K, Taniguchi M, Ishii Y. 2016. Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity. Eur J Immunol 46:1691–1703. doi: 10.1002/eji.201545987. [DOI] [PubMed] [Google Scholar]
- 186.Maartens G, Celum C, Lewin SR. 2014. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 384:258–271. doi: 10.1016/S0140-6736(14)60164-1. [DOI] [PubMed] [Google Scholar]
- 187.Levy JA. 1993. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 57:183–289. doi: 10.1128/MMBR.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Moll M, Andersson SK, Smed-Sörensen A, Sandberg JK. 2010. Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments. Blood 116:1876–1884. doi: 10.1182/blood-2009-09-243667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 189.van der Vliet HJJ, von Blomberg BME, Hazenberg MD, Nishi N, Otto SA, van Benthem BH, Prins M, Claessen FA, van den Eertwegh AJM, Giaccone G, Miedema F, Scheper RJ, Pinedo HM. 2002. Selective decrease in circulating Vα24+ Vβ11+ NKT cells during HIV type 1 infection. J Immunol 168:1490–1495. doi: 10.4049/jimmunol.168.3.1490. [DOI] [PubMed] [Google Scholar]
- 190.Motsinger A, Haas DW, Stanic AK, Van Kaer L, Joyce S, Unutmaz D. 2002. CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection. J Exp Med 195:869–879. doi: 10.1084/jem.20011712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 191.Moll M, Snyder-Cappione J, Spotts G, Hecht FM, Sandberg JK, Nixon DF. 2006. Expansion of CD1d-restricted NKT cells in patients with primary HIV-1 infection treated with interleukin-2. Blood 107:3081–3083. doi: 10.1182/blood-2005-09-3636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Sandberg JK, Fast NM, Palacios EH, Fennelly G, Dobroszycki J, Palumbo P, Wiznia A, Grant RM, Bhardwaj N, Rosenberg MG, Nixon DF. 2002. Selective loss of innate CD4+ V 24 natural killer T cells in human immunodeficiency virus infection. J Virol 76:7528–7534. doi: 10.1128/jvi.76.15.7528-7534.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 193.Vasan S, Poles MA, Horowitz A, Siladji EE, Markowitz M, Tsuji M. 2007. Function of NKT cells, potential anti-HIV effector cells, are improved by beginning HAART during acute HIV-1 infection. Int Immunol 19:943–951. doi: 10.1093/intimm/dxm055. [DOI] [PubMed] [Google Scholar]
- 194.Burza S, Croft SL, Boelaert M. 2018. Leishmaniasis. Lancet 392:951–970. doi: 10.1016/S0140-6736(18)31204-2. [DOI] [PubMed] [Google Scholar]
- 195.Tacchini-Cottier F, Weinkopff T, Launois P. 2012. Does T helper differentiation correlate with resistance or susceptibility to infection with L. major? Some insights from the murine model. Front Immunol 3:32. doi: 10.3389/fimmu.2012.00032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Amprey JL, Im JS, Turco SJ, Murray HW, Illarionov PA, Besra GS, Porcelli SA, Späth GF. 2004. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J Exp Med 200:895–904. doi: 10.1084/jem.20040704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197.Robert-Gangneux F, Drogoul AS, Rostan O, Piquet-Pellorce C, Cayon J, Lisbonne M, Herbelin A, Gascan H, Guiguen C, Samson M, Gangneux JP. 2012. Invariant NKT cells drive hepatic cytokinic microenvironment favoring efficient granuloma formation and early control of Leishmania donovani infection. PLoS One 7:e33413. doi: 10.1371/journal.pone.0033413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Kumari S, Jamal F, Shivam P, Thakur A, Kumar M, Bimal S, Das VNR, Pandey K, Narayan S, Gupta AK, Das P, Singh SK. 2015. Leishmania donovani skews the CD56+ natural killer T cell response during human visceral leishmaniasis. Cytokine 73:53–60. doi: 10.1016/j.cyto.2015.01.011. [DOI] [PubMed] [Google Scholar]
- 199.Kumari S, Shivam P, Kumar S, Jamal F, Singh MK, Bimal S, Narayan S, Pandey K, Das VNR, Das P, Singh SK. 2018. Leishmania donovani mediated higher expression of CCL4 induces differential accumulation of CD4+CD56+ NKT and CD8+CD56+ NKT cells at infection site. Cytokine 110:306–315. doi: 10.1016/j.cyto.2018.03.022. [DOI] [PubMed] [Google Scholar]
- 200.Kumari S, Shivam P, Hansa J, Jamal F, Singh MK, Bimal S, Narayan S, Pandey K, Das VNR, Das P, Singh SK. 2018. CD8dim but not CD8bright cells positive to CD56 dominantly express KIR and are cytotoxic during visceral leishmaniasis. Hum Immunol 79:616–620. doi: 10.1016/j.humimm.2018.05.004. [DOI] [PubMed] [Google Scholar]
- 201.Mattner J, Donhauser N, Werner-Felmayer G, Bogdan C. 2006. NKT cells mediate organ-specific resistance against Leishmania major infection. Microbes Infect 8:354–362. doi: 10.1016/j.micinf.2005.07.002. [DOI] [PubMed] [Google Scholar]
- 202.Joyee AG, Uzonna J, Yang X. 2010. Invariant NKT cells preferentially modulate the function of CD8α+ dendritic cell subset in inducing type 1 immunity against infection. J Immunol 184:2095–2106. doi: 10.4049/jimmunol.0901348. [DOI] [PubMed] [Google Scholar]
- 203.Griewank KG, Lorenz B, Fischer MR, Boon L, Lopez Kostka S, von Stebut E. 2014. Immune modulating effects of NKT cells in a physiologically low dose Leishmania major infection model after αGalCer analog PBS57 stimulation. PLoS Negl Trop Dis 8:e2917. doi: 10.1371/journal.pntd.0002917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204.White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. 2014. Malaria. Lancet 383:723–735. doi: 10.1016/S0140-6736(13)60024-0. [DOI] [PubMed] [Google Scholar]
- 205.de Souza JB, Hafalla JCR, Riley EM, Couper KN. 2010. Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology 137:755–772. doi: 10.1017/S0031182009991715. [DOI] [PubMed] [Google Scholar]
- 206.Gonzalez-Aseguinolaza G, de Oliveira C, Tomaska M, Hong S, Bruna-Romero O, Nakayama T, Taniguchi M, Bendelac A, Van Kaer L, Koezuka Y, Tsuji M. 2000. alpha-Galactosylceramide-activated Valpha 14 natural killer T cells mediate protection against murine malaria. Proc Natl Acad Sci U S A 97:8461–8466. doi: 10.1073/pnas.97.15.8461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Soulard V, Roland J, Sellier C, Gruner AC, Leite-de-Moraes M, Franetich J-F, Renia L, Cazenave P-A, Pied S. 2007. Primary infection of C57BL/6 mice with Plasmodium yoelii induces a heterogeneous response of NKT cells. Infect Immun 75:2511–2522. doi: 10.1128/IAI.01818-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 208.Li X, Huang J, Kaneko I, Zhang M, Iwanaga S, Yuda M, Tsuji M. 2017. A potent adjuvant effect of a CD1d-binding NKT cell ligand in human immune system mice. Expert Rev Vaccines 16:73–80. doi: 10.1080/14760584.2017.1256208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann CC, Wilson JM, Schmieg J, Kronenberg M, Nakayama T, Taniguchi M, Koezuka Y, Tsuji M. 2002. Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines. J Exp Med 195:617–624. doi: 10.1084/jem.20011889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 210.Hansen DS, Siomos MA, de Koning-Ward T, Buckingham L, Crabb BS, Schofield L. 2003. CD1d-restricted NKT cells contribute to malarial splenomegaly and enhance parasite-specific antibody responses. Eur J Immunol 33:2588–2598. doi: 10.1002/eji.200323666. [DOI] [PubMed] [Google Scholar]