Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Apr 1.
Published in final edited form as: Curr Opin Immunol. 2013 Feb 4;25(2):168–173. doi: 10.1016/j.coi.2013.01.002

Natural Killer T cell obsession with self-antigens

Laurent Gapin 1, Dale I Godfrey 2, Jamie Rossjohn 3
PMCID: PMC3646945  NIHMSID: NIHMS437562  PMID: 23384972

Summary

Natural Killer T cells are distinct lymphocyte lineages that recognize lipid antigens presented by the non-classical MHC molecule CD1d. Two categories of NKT cells, type I and type II, have been described based on T-cell receptor expression and antigenic specificity. In both cases, the recognition of self-antigens by these cells plays an important role not only in their development but also in their regulation of a broad range of immune responses. Here we review recent advances in our understanding of how and when NKT cell autoreactivity manifests itself, how the NKT TCR engages self-antigens and the nature of these self-antigens.

Introduction

The term Natural Killer T (NKT) cells was framed about 20 years ago to define a population of mature T cells found within the mouse thymus, with the ability to secrete several effector cytokines in the absence of prior foreign antigen priming. These cells were identified phenotypically by the expression of several activation/memory surface markers and, in C57BL/6 mice, the NK1.1 marker, which is usually associated with the NK lineage. NKT cells also distinguish themselves by recognizing lipid antigens presented by the Major Histocompatibility Complex (MHC) class I-like molecule CD1d, in contrast with “conventional” T cells that are directed at peptide antigens presented by MHC molecules.

NKT cells are divided into type I and type II subsets [1]. The most prevalent NKT cells in mice are the type-I-NKT cells which express semi-invariant T cell receptors (TCRs) made of a canonical germline-encoded TCR α rearrangement between the variable (V) α14 and joining (J) α18 gene segments associated with a biased set of Vβ chains (Vβ8.2, Vβ7 and Vβ2) with non-germline encoded diversity in their complementary determinant region (CDR) 3β. A similar population of type-I-NKT cells using the Vα24-Jα18 and Vβ11 TCR genes (paralogues of the Vα14 and Vβ8 mouse gene segments, respectively) are found in humans. Type-I-NKT cells are responsive to the marine sponge-derived antigen α-galactosylceramide (αGC) when presented by CD1d molecules. This contrast with type-II-NKT cells, which do not react with αGC and express a much more diverse TCR repertoire [2]. The antigenic specificity of type II cells is only starting to emerge [3], with some type II NKT cells being reactive to the self-antigens such as sulfatide [4,5] and β-glucosylceramide [6], but their functional and phenotypical characterization remains mostly unclear.

The development of CD1d tetramer loaded with αGC has allowed investigators to track and specifically study type-I-NKT cells based solely on their Ag-reactivity. This has revealed that, despite their conserved reactivity to αGC, αGC-CD1d tetramer+ cells are composed of several phenotypically and functionally different subpopulations [7]•[8].

Amongst the many unique characteristics of type-I-NKT cells, one stands out in particular. Namely, type-I-NKT cells tend to be autoreactive, meaning that they can respond to CD1d-expressing antigen presenting cells (APCs) in the absence of any external antigen. Therefore, in addition to recognizing several different microbe-derived and synthetic antigens [9], type-I-NKT cells also have a dual reactivity for self-antigen(s). This underlying autoreactivity has obvious implications for the role that type-I-NKT cells play in regulating immune responses, including cancer, autoimmunity, graft rejection and graft versus host disease but also, more recently, in controlling metabolism [10-13]••. Here, we review recent advances made in the identification of CD1d-restricted self-antigens, and the recognition thereof, by type-I-NKT cells.

Recent evidence of type-I-NKT cell autoreactivity in vivo

A transgenic mouse model expressing GFP under the control of the TCR-signaling induced transcription factor Nr4a1 (Nur77) promoter as a means to measure the strength of TCR stimulus directly in vivo, demonstrated that type-I-NKT cells express high levels of GFP immediately after selection in the thymus and lose most GFP expression after maturation and export to the periphery [14]••. This suggests that NKT cells might not continually perceive autoreactive stimuli once they mature and migrate to the periphery. Alternatively, weak TCR stimulation through the recognition of self-antigen(s) might not lead to the full activation of type-I-NKT cells but may nevertheless have important consequences, such as epigenetic modifications at cytokine loci [15]. Yet, another model using an IFN-γ-inducible cytoplasmic protein as a reporter, showed, in unchallenged mice, intense expression in small foci with type-I-NKT cells present at the center of these foci [16]•. Altogether, these results suggest that type-I-NKT cells have the underlying capacity to sense CD1d-restricted self-antigen(s) and this autoreactivity can be unleashed when combined with inflammatory cytokines released by APCs, even in the context of infection where foreign glycolipid antigens are also present [8,17-19]•. Therefore, identification of the self-lipids that are involved in this autoreactivity, and determining how type-I-NKT TCRs recognize them, is key for our understanding of the biological relevance of these cells and for harnessing their therapeutic potential.

How does the type-I-NKT TCR recognize “self”?

Most microbe-derived type-I-NKT cell antigens share a common characteristic: a lipid backbone attached to a sugar moiety via an α-glycosidic linkage [20]. This α-linkage causes the sugar to lie flat along the CD1d antigen-binding groove. However, most mammalian glycolipids have β-glycosidic linkages, which cause the sugar head group to protrude perpendicular to the CD1d antigen-binding groove and it was unclear how the type-I-NKT TCR could recognize such chemically distinct Ags. Two recent studies [21]•• and [22]•• shed light on this conundrum. Instead of the type-I-NKT TCR “adapting” to the protruding perpendicular β-linked self-antigens, it flattens the self-antigens into an α-like conformation that mimics the recognition of foreign antigens. This form of induced-fit molecular mimicry necessitates the repositioning of the β-linked antigens, incurring a considerable energetic penalty upon binding of the type-I-NKT TCR to the β-antigen-CD1d complex. These low affinity interactions for self-antigen(s) might be important for selecting an appropriate type-I-NKT TCR repertoire during development, retaining weak affinity for self-antigens but stronger, high affinity interactions with foreign, α-linked antigens.

Triggering a type-I-NKT autoreactive response

With a relatively low affinity for self-antigen, how do type-I-NKT cells achieve an activation state when faced with autoreactivity? Several possibilities exist.

First, under certain circumstances, the activation and natural functions of type-I-NKT cells in vivo appear to be CD1d and TCR independent [23,24]. Exposure to IL-12 and IL-18 [25] or IL-12 and type I-interferons [24] can be sufficient to activate type-I-NKT cells. The neurotransmitter noradrenaline was also recently shown to modulate the activation and behavior of type-I-NKT cells in vivo in a CD1d-independent manner [26]••.

Second, inflammatory cytokines, upregulation of CD1d expression levels, and/or of co-stimulatory molecules might help reach the activation threshold necessary to activate type-I-NKT cells. Diminishing the expression of ligands for inhibitory receptors (such as NK receptors) expressed by type-I-NKT cells may also modulate the autoreactivity threshold (see ref [27] for review).

Third, we [28]••, and others [29]••, recently showed that the type-I-NKT TCR autoreactivity can occur due to the presence of unique sequences within the hypervariable CDR3β loop, which can profoundly influence type-I NKT TCR affinity for CD1d presenting self-antigens. For example, CDR3β sequences encoding a hydrophobic motif promoted self-association of the type-I-NKT TCR with CD1d, although other CDR3β sequences lacking this motif can achieve an analogous effect. Thus, type-I-NKT cell autoreactivity can arise from the direct interaction between CD1d and the type-I-NKT TCR resulting in the accommodation of a broad range of CD1d-restricted self-antigens in a consensus NKT TCR-CD1d-Ag docking mode that is underpinned by germline-encoded recognition of the CD1d-Ag complex [28,30-32]. The type of self-antigen is still important however, as demonstrated when several self-lipids, when presented by CD1d molecules, were found to “hinder” the binding of the highly autoreactive type-I-like NKT TCR [28]••. CD1d molecules at the surface of APCs are loaded with a variety of different self-antigens including some “bulky” or rigid ones [33-36]. Thus, we suggest that type-I-NKT autoreactivity may in part result from a shift in the balance of permissive versus hindering self-antigens that are presented by CD1d-restricted on the cell surface.

Fourth, a limited number of self-antigens may specifically mediate the autoreactivity of type-I-NKT cells (Figure 1). These antigen(s) might be under-represented in the steady state, but induced and presented by CD1d molecules at the surface of APCs following particular inflammatory stimuli [17-19].

Figure 1. NKT cell self-antigens.

Figure 1

Open in a new tab

The chemical structure of the various self-antigens currently reported for NKT cells is shown. The type of NKT cells for which antigen reactivity has been shown is indicated by +, while absence of reactivity is indicated by −. A schematic of NKT TCR – CD1d interaction is depicted with the arrow indicating the presence of the self-antigen(s) within the groove of the CD1d molecule. iGb3, isoglobotrihexosylceramide; β-GlcCer, β-D-glucopyranosylceramide; pLPE, ether-bonded lysophosphatidylethanolamine; eLPA, ether-bonded lysophosphatidic acid; LPE, lysophosphatidylethanolamine; LPC, lysophosphatidylcholine; LSM, lysosphingomyelin.

Type-I-NKT cell autoreactivity: which antigen(s)?

Amongst the many potential self-antigen candidates, the β-linked isoglobotrihexosylceramide (iGb3) was shown to activate type-I-NKT cells in a cell-free system [37], making it a good candidate for type-I-NKT self-antigen, with a potential role for their development in the thymus. However, the scarcity of iGb3 in mouse thymus and APCs [38], the absence of type-I-NKT cell defect in mice lacking the iGb3 synthase [39], and the lack of functional iGb3 synthase in humans [40], collectively challenged the concept that iGb3 is a key self-antigen involved in the positive selection of type-I-NKT cells. Nonetheless, iGb3 certainly is a low affinity self-antigen for mouse type-I-NKT cells and may therefore play a role in type-I-NKT cell autoreactivity under particular circumstances.

A panel of naturally occurring GSLs was recently screened for antigenic activity on type-I-NKT cells [41]•. Surprisingly, the precursor of most GSLs outside of the central nervous system, β-D-glucopyranosylceramide (β-GlcCer) potently activated mouse and human type-I-NKT cells in a CD1d-restricted manner. Interestingly, β-GlcCer synthesis is enhanced leading to accumulation of this glycolipid within APCs after LPS stimulation and in vivo after bacterial infection, and inhibition of this process reduced type-I-NKT cell autoreactivity [41]•. This suggests that the presentation of β-GlcCer by CD1d molecules might contribute to the stimulation of type-I-NKT cells in a multitude of pathological contexts in the absence of foreign lipid antigens. However, it should also be noted that the modulation of β-GlcCer levels in APCs can affect the expression of several co-stimulatory molecules and cytokines, including IL-12 [42]. How presentation of this glycolipid, an abundant ceramide in cells [43], is regulated to avert constant stimulation of type-I-NKT cells in vivo remains to be addressed.

To identify lipids that might be involved in the development of type-I-NKT cells, Facciotti et al. fractionated lipids from mouse thymocytes according to polarity and size [44]•. They identified the peroxisome-generated, ether-bonded plasmalogens, lysophosphatidylethanolamine (pLPE) and lysophosphatidic acid (eLPA), as self-lipids capable of stimulating freshly isolated mouse and human type-I-NKT cells when presented by CD1d molecules in an APC-free assay, but they did not find any agonistic activity for the GSL-containing fractions, presumably including β-GlcCer [44]•. These findings are in contrast with the study from Brennan and colleagues [41]• that showed substantial levels of β-GlcCer present in the mouse thymus and β-GlcCer-containing fractions purified from mouse thymus readily stimulating type-I-NKT cells [41]•. Yet, the results are in agreement with a previous study that showed that GSL biosynthesis defect in APCs does not disturb the autoreactivity of type-I-NKT cells [45]. Interestingly, only the ether-bonded versions of the lysophospholipids stimulated both thymic and peripheral type-I-NKT cells [33]•, while the common glycerophospholipids LPE and LPA, which contain a fatty acid rather than a fatty alcohol [46], did not [47]. In contrast, LPE, which is induced following hepatitis B viral infection, can be a potential self-antigen for some type-II-NKT cells [47]. Moreover, this study showed that type-I-NKT cells may also respond to self-phospholipid antigens in the context of hepatitis B infection, although their precise identity was not determined [47]. The specific role for the ether bond in the stimulation of type-I-NKT cells remains to be explored.

Other potentially relevant self-antigens for type-I-NKT cells include lysophosphatidylcholine (LPC) and lysosphingomyelin, which can be found at elevated levels during inflammatory responses [48]•[49]. These two self-antigens weakly stimulate some human type-I-NKT cells [48]• but apparently fail to trigger a response by mouse type-I-NKT cells [41,44,45]•. This raises the possibility that mouse and human self-antigen(s) for type-I-NKT cells might be distinct, due to differing trafficking requirements and sequence differences between mouse and human CD1d [50]. Further, differences in the fine specificity of human and mouse type-I-NKT cells for the recognition of α-GalCer analogues have been reported [51].

Taken together, it seems likely that there is not simply one self-antigen for type-I-NKT cells but rather several different self-antigens with various structures might be capable of providing an agonistic signal when recognized by the type-I-NKT TCR.

Back to the future

As NKT cell functions are likely mediated through their recognition of “self”, developing a mouse model specifically lacking type-I-NKT cells (the Jα18 knockout) was key to the study of type-I-NKT and type-II-NKT cells [52]. However, recent high throughput sequencing of TCRα rearrangements from CD4+CD8+ (DP) thymocytes of CD1d−/− and Jα18−/− mice [53]•• revealed that transcripts encoding Jα genes located upstream of the Jα18 in the Jα locus were essentially absent from samples derived from Jα18−/− mice, indicating that the repertoire of other T lymphocyte populations is severely impaired in these mice.

Non-productive rearrangements were also affected in these mice, most likely due to the inadvertent effect that the PGK-neor cassette has on transcription and gene rearrangements [54]. Two independent colonies of Jα18−/− mice, maintained separately for over 10 years, were affected, suggesting a common effect within the original strain. However, a population of αGC/CD1d-reactive NKT cells with a TCRα chain using an upstream Jα gene segment (Vα10-Jα50) was recently identified in Jα18−/− mice [55]•, implying that not all colonies might be affected or that some upstream Jα transcripts might still be expressed, albeit at much reduced levels, and can be utilized by the NKT cell repertoire.

Nonetheless, the consequences of this unanticipated finding are potentially far reaching, because they raise the question of whether some results that have been generated with Jα18−/− mice, might, at least in part, be attributed to the change in TCR repertoire diversity, rather than the absence of type-I NKT cells. Further, as many studies of type-II-NKT cells have relied on observed differences between Jα18−/− and CD1d−/− mice to indicate a presumed role for type-II-NKT cells, we suggest that the doubly deficient strain (Jα18−/− x CD1d−/−) might serve as a more appropriate control.

Conclusions and future directions

While the past few years have provided us with a wealth of information as to how different self-lipids are recognized by the type-I-NKT TCR (reviewed in [20,56]), the next challenge will be to understand when, where and in which conditions the orchestration of the presentation of these various self-antigens by CD1d occurs and how type-I-NKT cells might differentially respond to them. It will also be important to address the mechanisms of type-II-NKT cell autoreactivity and how this differs from type-I-NKT cell autoreactivity. Recent insights into type II autoreactivity were provided by solving the crystal structure of a type II NKT TCR recognizing sulfatide/lysosulfatide [57,58]••, an abundant class of lipid-antigens in neuronal tissue. It remains to be seen whether other type II NKT cells exhibit differing patterns of autoreactivity. Finally, developing the appropriate reagents to directly detect autoreactive type-I and type-II NKT cells will ultimately allow the field to assess the autoreactive potential of all CD1d-restricted NKT subsets and their role in health and disease.

Highlights.

  • NKT cells are inherently reactive to self-antigens presented by CD1d molecules

  • Self-antigens are made to mimic foreign antigens upon recognition by type-I NKT TCRs

  • There are multiple ways to trigger a type-I NKT response in vivo

  • Several different self-antigens can stimulate type-I NKT cells

  • The main mouse model for the study of type-I NKT cell autoreactivity is imperfect

Acknowledgements

We apologize to colleagues whose works were not cited due to space constraints or omission. We thank members of our respective laboratories and Drs. Philippa Marrack and Olivier Lantz for fruitful discussions. This work was supported by National Institutes of Health Grants (AI092108, AI090450), the Australian Research Council, and the National Health and Medical Research Council of Australia (NHMRC). DIG is supported by an NHMRC Senior Principal Research Fellowship; JR by an NHMRC Australia Fellowship.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol. 2004;4:231–237. doi: 10.1038/nri1309. [DOI] [PubMed] [Google Scholar]
  • 2.Kadri N, Blomqvist M, Cardell SL. Type II natural killer T cells: a new target for immunomodulation? Expert Rev Clin Immunol. 2008;4:615–627. doi: 10.1586/1744666X.4.5.615. [DOI] [PubMed] [Google Scholar]
  • 3.Rhost S, Sedimbi S, Kadri N, Cardell SL. Immunomodulatory Type II Natural Killer T Lymphocytes in Health and Disease. Scand J Immunol. 2012;76:246–255. doi: 10.1111/j.1365-3083.2012.02750.x. [DOI] [PubMed] [Google Scholar]
  • 4.Blomqvist M, Rhost S, Teneberg S, Löfbom L, Østerbye T, Brigl M, Månsson J-E, Cardell SL. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur J Immunol. 2009:1726–1735. doi: 10.1002/eji.200839001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Jahng A, Maricic I, Aguilera C, Cardell SL, Halder R, Kumar V. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med. 2004;199:947–957. doi: 10.1084/jem.20031389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Rhost S, Lofbom L, Rynmark BM, Pei B, Mansson JE, Teneberg S, Blomqvist M, Cardell SL. Identification of novel glycolipid ligands activating a sulfatide-reactive, CD1d-restricted, type II natural killer T lymphocyte. Eur J Immunol. 2012 doi: 10.1002/eji.201142350. [DOI] [PubMed] [Google Scholar]
  • • 7.Watarai H, Sekine-Kondo E, Shigeura T, Motomura Y, Yasuda T, Satoh R, Yoshida H, Kubo M, Kawamoto H, Koseki H, et al. Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines. PLoS Biol. 2012;10:e1001255. doi: 10.1371/journal.pbio.1001255. This manuscript describes new subsets of type-I-NKT cells that uniquely expresses the IL-17RB receptor (i.e. the IL-25 receptor) and respond to IL-25 by secreting large amounts of Th2 and Th17 cytokines.
  • 8.Doisne JM, Soulard V, Becourt C, Amniai L, Henrot P, Havenar-Daughton C, Blanchet C, Zitvogel L, Ryffel B, Cavaillon JM, et al. Cutting edge: crucial role of IL-1 and IL-23 in the innate IL-17 response of peripheral lymph node NK1.1-invariant NKT cells to bacteria. J Immunol. 2011;186:662–666. doi: 10.4049/jimmunol.1002725. [DOI] [PubMed] [Google Scholar]
  • 9.Kinjo Y, Kronenberg M. Detection of microbes by natural killer T cells. Adv Exp Med Biol. 2009;633:17–26. doi: 10.1007/978-0-387-79311-5_3. [DOI] [PubMed] [Google Scholar]
  • •• 10.Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O’Shea D, O’Farrelly C, Exley MA. Adipose Tissue Invariant NKT Cells Protect against Diet-Induced Obesity and Metabolic Disorder through Regulatory Cytokine Production. Immunity. 2012;37:574–587. doi: 10.1016/j.immuni.2012.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 11.Ji Y, Sun S, Xia S, Yang L, Li X, Qi L. Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem. 2012;287:24378–24386. doi: 10.1074/jbc.M112.371807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 12.Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks-Shulman PA, Tamboli RA, Kim S, Mendez-Fernandez YV, Besra GS, Lomenick JP, et al. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci U S A. 2012;109:E1143–1152. doi: 10.1073/pnas.1200498109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 13.Schipper HS, Rakhshandehroo M, van de Graaf SF, Venken K, Koppen A, Stienstra R, Prop S, Meerding J, Hamers N, Besra G, et al. Natural killer T cells in adipose tissue prevent insulin resistance. J Clin Invest. 2012;122:3343–3354. doi: 10.1172/JCI62739. Collectively, references 10-13 demonstrate a previously unrecognized role for type-I-NKT cells in metabolism homeostasis.
  • •• 14.Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS, Punt J, Hogquist KA. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med. 2011;208:1279–1289. doi: 10.1084/jem.20110308. This manuscript describes a new mouse models in which GFP expression is linked to the Nur77 promoter, allowing the strength of TCR stimulus to be reported directly in vivo. Interestingly, type-I-NKT cells are GFP+ immediately following positive selection in the thymus and lose GFP expression during maturation and after export to the periphery.
  • 15.Wang X, Bishop KA, Hegde S, Rodenkirch LA, Pike JW, Gumperz JE. Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. J Exp Med. 2012;209:987–1000. doi: 10.1084/jem.20111024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • • 16.Zeng J, Howard JC. Spontaneous focal activation of invariant natural killer T (iNKT) cells in mouse liver and kidney. BMC Biol. 2010;8:142. doi: 10.1186/1741-7007-8-142. This manuscript used the interferon-γ-inducible protein Irga6 as a histological marker for local IFN-γ production. The authors found intense expression of Irg6 in small foci in the liver and kidneys of unchallenged mice. The expression was dependent on IFN-γ secreted by T cells in the centres of these foci. The T cells were identified as type-I-NKT cells.
  • 17.Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol. 2003;4:1230–1237. doi: 10.1038/ni1002. [DOI] [PubMed] [Google Scholar]
  • 18.Paget C, Mallevaey T, Speak AO, Torres D, Fontaine J, Sheehan KC, Capron M, Ryffel B, Faveeuw C, Leite de Moraes M, et al. Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity. 2007;27:597–609. doi: 10.1016/j.immuni.2007.08.017. [DOI] [PubMed] [Google Scholar]
  • • 19.Brigl M, Tatituri RV, Watts GF, Bhowruth V, Leadbetter EA, Barton N, Cohen NR, Hsu FF, Besra GS, Brenner MB. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med. 2011;208:1163–1177. doi: 10.1084/jem.20102555. This manuscript argues that a combination of inflammatory cytokines and recognition of self-antigen(s) presented by CD1d molecules is responsible for the activation of type-I-NKT cells during bacterial infection, irrespective of whether or not the bacteria carries antigens that are known to activate type-I-NKT cells.
  • 20.Rossjohn J, Pellicci DG, Patel O, Gapin L, Godfrey DI. Natural killer T cell antigen receptor recognition of CD1d-restricted antigens. Nature Reviews Immunology. 2012 doi: 10.1038/nri3328. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 21.Pellicci DG, Clarke AJ, Patel O, Mallevaey T, Beddoe T, Le Nours J, Uldrich AP, McCluskey J, Besra GS, Porcelli SA, et al. Recognition of beta-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat Immunol. 2011;12:827–833. doi: 10.1038/ni.2076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 22.Yu ED, Girardi E, Wang J, Zajonc DM. Cutting edge: structural basis for the recognition of beta-linked glycolipid antigens by invariant NKT cells. J Immunol. 2011;187:2079–2083. doi: 10.4049/jimmunol.1101636. Collectively, references 21 and 22 explain how the TCR expressed by type-I-NKT cells can structurally accommodate the recognition of self-glycolipids, which are inherently chemically different from foreign NKT cell antigens.
  • 23.Novak J, Beaudoin L, Park S, Griseri T, Teyton L, Bendelac A, Lehuen A. Prevention of type 1 diabetes by invariant NKT cells is independent of peripheral CD1d expression. J Immunol. 2007;178:1332–1340. doi: 10.4049/jimmunol.178.3.1332. [DOI] [PubMed] [Google Scholar]
  • 24.Wesley JD, Tessmer MS, Chaukos D, Brossay L. NK cell-like behavior of Vα14i NK T cells during MCMV infection. PLoS Pathog. 2008;4:e1000106. doi: 10.1371/journal.ppat.1000106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Nagarajan NA, Kronenberg M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol. 2007;178:2706–2713. doi: 10.4049/jimmunol.178.5.2706. [DOI] [PubMed] [Google Scholar]
  • • 26.Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011;334:101–105. doi: 10.1126/science.1210301. This manuscript shows an important role played by type-I-NKT cells in biasing the overall immune response towards a Th2 phenotype following stroke. The stimulation of type-I-NKT cells appears to be CD1d-independent and is instead mediated by adrenergic neurotransmitters.
  • 27.Gapin L. iNKT cell autoreactivity; what is ‘self’ and how is it recognized? Nat Rev Immunol. 2010;10:272–277. doi: 10.1038/nri2743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 28.Mallevaey T, Clarke AJ, Scott-Browne JP, Young MH, Roisman LC, Pellicci DG, Patel O, Vivian JP, Matsuda JL, McCluskey J, et al. A molecular basis for NKT cell recognition of CD1d-self-antigen. Immunity. 2011;34:315–326. doi: 10.1016/j.immuni.2011.01.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 29.Matulis G, Sanderson JP, Lissin NM, Asparuhova MB, Bommineni GR, Schumperli D, Schmidt RR, Villiger PM, Jakobsen BK, Gadola SD. Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3β loop. PLoS Biol. 2010;8:e1000402. doi: 10.1371/journal.pbio.1000402. Collectively, references 28 and 29 demonstrate that the sequence of the CDR3β loop of the type-I-NKT TCR strongly influences the affinity of the TCR for the antigen-CD1d complex and thereby the autoreactivity of the cells bearing these TCRs. Importantly, modulation of the affinity is antigen independent, suggesting that multiple antigens, including self-antigens, can be recognized similarly by the type-I-NKT TCR.
  • 30.Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R, Besra GS, Bharadwaj M, Godfrey DI, McCluskey J, et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature. 2007;448:44–49. doi: 10.1038/nature05907. [DOI] [PubMed] [Google Scholar]
  • 31.Scott Browne J, Matsuda JL, Mallevaey T, Borg NA, White J, McCluskey J, Rossjohn J, Kappler J, Marrack P, Gapin L. Germline-encoded recognition of diverse glycolipids by NKT cells. Nat Immunol. 2007;8:1105–1113. doi: 10.1038/ni1510. [DOI] [PubMed] [Google Scholar]
  • 32.Wun KS, Borg NA, Kjer-Nielsen L, Beddoe T, Koh R, Richardson SK, Thakur M, Howell AR, Scott-Browne JP, Gapin L, et al. A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR. J Exp Med. 2008;205:939–949. doi: 10.1084/jem.20072141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Cox D, Fox L, Tian R, Bardet W, Skaley M, Mojsilovic D, Gumperz J, Hildebrand W. Determination of cellular lipids bound to human CD1d molecules. PLoS ONE. 2009;4(5):e5325. doi: 10.1371/journal.pone.0005325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Muindi K, Cernadas M, Watts GFM, Royle L, Neville DCA, Dwek RA, Besra GS, Rudd PM, Butters TD, Brenner MB. Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d. Proc Natl Acad Sci U S A. 2010;107:3052–3057. doi: 10.1073/pnas.0915056107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Yuan W, Kang SJ, Evans JE, Cresswell P. Natural lipid ligands associated with human CD1d targeted to different subcellular compartments. J Immunol. 2009;182:4784–4791. doi: 10.4049/jimmunol.0803981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Haig NA, Guan Z, Li D, McMichael A, Raetz CR, Xu XN. Identification of self-lipids presented by CD1c and CD1d proteins. J Biol Chem. 2011;286:37692–37701. doi: 10.1074/jbc.M111.267948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Zhou D, Mattner J, Cantu C, 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science. 2004;306:1786–1789. doi: 10.1126/science.1103440. [DOI] [PubMed] [Google Scholar]
  • 38.Porubsky S, Speak AO, Salio M, Jennemann R, Bonrouhi M, Zafarulla R, Singh Y, Dyson J, Luckow B, Lehuen A, et al. Globosides but not isoglobosides can impact the development of invariant NKT cells and their interaction with dendritic cells. J Immunol. 2012;189:3007–3017. doi: 10.4049/jimmunol.1201483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Porubsky S, Speak AO, Luckow B, Cerundolo V, Platt FM, Grone H-F. Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency. Proc Natl Acad Sci U S A. 2007;104:5977–5982. doi: 10.1073/pnas.0611139104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Christiansen D, Milland J, Mouhtouris E, Vaughan H, Pellicci DG, McConville MJ, Godfrey DI, Sandrin MS. Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. PLoS Biol. 2008;6:e172. doi: 10.1371/journal.pbio.0060172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • • 41.Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, Sanderson JP, Gadola SD, Hsu FF, Besra GS, Brenner MB. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat Immunol. 2011;12:1202–1211. doi: 10.1038/ni.2143. This study reports that β-GlcCer, the abundant precursor of most glycolipids, activates type-I-NKT cells. β-GlcCer is upregulated in APCs during infections and in response to Toll-like receptor agonist, contributing to the microbial activation of type-I-NKT cells.
  • 42.Pandey MK, Rani R, Zhang W, Setchell K, Grabowski GA. Immunological cell type characterization and Th1-Th17 cytokine production in a mouse model of Gaucher disease. Mol Genet Metab. 2012;106:310–322. doi: 10.1016/j.ymgme.2012.04.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Gault CR, Obeid LM, Hannun YA. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol. 2010;688:1–23. doi: 10.1007/978-1-4419-6741-1_1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • • 44.Facciotti F, Ramanjaneyulu GS, Lepore M, Sansano S, Cavallari M, Kistowska M, Forss-Petter S, Ni G, Colone A, Singhal A, et al. Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus. Nat Immunol. 2012;13:474–480. doi: 10.1038/ni.2245. This manuscript shows that the ether-bonded plasmalogens, pLPE and eLPA, which are both produced in the peroxysome, activates type-I-NKT cells. Further, deficiency in the non-redundant enzyme GNPAT, which is key to the synthesis of ether-bonded plasmalogens, affects the number and developmental program of type-I-NKT cells.
  • 45.Pei B, Speak AO, Shepherd D, Butters T, Cerundolo V, Platt FM, Kronenberg M. Diverse endogenous antigens for mouse NKT cells: self-antigens that are not glycosphingolipids. J Immunol. 2011;186:1348–1360. doi: 10.4049/jimmunol.1001008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822:1442–1452. doi: 10.1016/j.bbadis.2012.05.008. [DOI] [PubMed] [Google Scholar]
  • 47.Zeissig S, Murata K, Sweet L, Publicover J, Hu Z, Kaser A, Bosse E, Iqbal J, Hussain MM, Balschun K, et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med. 2012;18:1060–1068. doi: 10.1038/nm.2811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • • 48.Fox LM, Cox DG, Lockridge JL, Wang X, Chen X, Scharf L, Trott DL, Ndonye RM, Veerapen N, Besra GS, et al. Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biol. 2009;7(10):e1000228. doi: 10.1371/journal.pbio.1000228. This study shows that the endogenous lipid lyso-phosphatidylcholine is recognized as an antigen by a fraction of human type-I-NKT cells.
  • 49.Lopez-Sagaseta J, Sibener LV, Kung JE, Gumperz J, Adams EJ. Lysophospholipid presentation by CD1d and recognition by a human Natural Killer T-cell receptor. Embo J. 2012;31:2047–2059. doi: 10.1038/emboj.2012.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Chen X, Wang X, Keaton JM, Reddington F, Illarionov PA, Besra GS, Gumperz JE. Distinct endosomal trafficking requirements for presentation of autoantigens and exogenous lipids by human CD1d molecules. J Immunol. 2007;178:6181–6190. doi: 10.4049/jimmunol.178.10.6181. [DOI] [PubMed] [Google Scholar]
  • 51.Wun KS, Ross F, Patel O, Besra GS, Porcelli SA, Richardson SK, Keshipeddy S, Howell AR, Godfrey DI, Rossjohn J. Human and mouse type I Natural Killer T-cell antigen receptors exhibit different fine specificities for CD1d-antigen. J Biol Chem. 2012 doi: 10.1074/jbc.M112.412320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kanno M, Taniguchi M. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997;278:1623–1626. doi: 10.1126/science.278.5343.1623. [DOI] [PubMed] [Google Scholar]
  • •• 53.Bedel R, Matsuda JL, Brigl M, White J, Kappler J, Marrack P, Gapin L. Lower TCR repertoire diversity in Traj18-deficient mice. Nat Immunol. 2012;13:705–706. doi: 10.1038/ni.2347. Highthroughput sequencing of Vα14-Cα rearrangements in the thymus of CD1d and Jα18-deficient mice reveals that transcripts encoding for rearrangements involving Jα genes upstream of the Jα18 gene segment are largely diminished in Jα18-deficient mice.
  • 54.Riegert P, Gilfillan S. A conserved sequence block in the murine and human TCR Jα region: assessment of regulatory function in vivo. J Immunol. 1999;162:3471–3480. [PubMed] [Google Scholar]
  • 55.Uldrich AP, Patel O, Cameron G, Pellicci DG, Day EB, Sullivan LC, Kyparissoudis K, Kjer-Nielsen L, Vivian JP, Cao B, et al. A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen-recognition properties. Nat Immunol. 2011;12:616–623. doi: 10.1038/ni.2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Girardi E, Zajonc DM. Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells. Immunol Rev. 2012;250:167–179. doi: 10.1111/j.1600-065X.2012.01166.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 57.Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V, Zajonc DM. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol. 2012;13:851–856. doi: 10.1038/ni.2371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •• 58.Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP, Mallevaey T, Clarke AJ, Le Nours J, Theodossis A, Cardell SL, et al. Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat Immunol. 2012;13:857–863. doi: 10.1038/ni.2372. References 57 and 58 report the first crystal structures of a type-II-NKT TCR in complex with mouse CD1d presenting lysosulfatide or sulfatide, respectively.

RESOURCES