Abstract
Human natural killer (NK) cells are innate lymphoid cells that mediate important effector functions in the control of viral infection and malignancy. Their ability to distinguish ‘self’ from ‘non-self’ and lyse virally infected and tumorigenic cells through germline-encoded receptors makes them important players in maintaining human health and a powerful tool for immunotherapeutic applications and fighting disease. Here, I introduce our current understanding of NK cell biology, including key facets of NK cell differentiation and the acquisition and execution of NK cell effector function. Further, the clinical relevance of NK cells in both primary immunodeficiency and immunotherapy is addressed. Together, this review is intended to provide an up-to-date and comprehensive overview of this important and interesting innate immune effector cell subset.
Keywords: Natural killer cells, cytotoxicity, innate lymphoid cells
Introduction
Natural killer (NK) cells are commonly described as being “innate immune effector cells that can lyse virally infected and tumorigenic cells without prior antigen sensitization”1–3. This fundamental description arises from the properties first attributed to NK cells upon their discovery almost 50 years ago. Since then, the study of human NK cell biology and the role that NK cells play in health and disease have revealed deeper knowledge about each aspect of that description, including their innate and adaptive properties, mechanisms of function, and role in controlling human disease and cancer. Here I will highlight recent advances in our understanding of NK cell etiology and function, including new insights into the clinical relevance of NK cells and their important role in our arsenal of immunotherapeutic tools.
NK cells are innate lymphoid cells (ILCs) that mediate primary functions of cellular cytotoxicity and cytokine production in the absence of rearranged antigen receptors4. Instead, a host of NK cell activating and inhibitory receptors recognize conserved molecular patterns, allowing them to quickly execute function and act as a first line of defense against infection and cellular transformation. NK cell cytotoxic function is primarily exerted through the formation of an immunological synapse, a specialized signaling platform that promotes the directed secretion of specialized secretory lysosomes, termed lytic granules, that contain perforin and granzymes5. NK cell effector function is dictated by a balance of activating and inhibitory receptors, including the killer immunoglobulin-like receptors (KIRs), the low affinity Fc receptor CD16, and other natural cytotoxicity receptors (reviewed in6). NK cells are also rapid producers of cytokines, particularly type II interferon (IFNγ) and tumor necrosis factorα (TNFα), but also granulocyte and macrophage colony sensing factor (GM-CSF), interleukins −10, −5, −8 and −13, and chemokines including CC motif chemokine ligands 3 and −4 (CCL3 and CCL4) [macrophage inflammatory protein 1α and -β], and CCL5 [Regulated on Activation, Normal T cell Expressed and Secreted (RANTES)]7–9. Given their innate sensing mechanisms, NK cells are frontline defenders against viral infection and malignant transformation, and their innate effector functions have demonstrable importance for maintaining human health. While it is beyond the scope of this review to cover ILC subsets, new insights into the functional relationship between NK cells and particularly ILC1 cells may be of interest to readers and has been recently reviewed elsewhere10. Finally, their intrinsic properties of rapid activation have made NK cells attractive tools for immunotherapeutic approaches11.
Human NK cell subsets
Human NK cells can be isolated from tissues including liver, lungs, uterus, intestine, lymph node, and skin, and, most commonly, from peripheral blood12. The most referenced peripheral blood NK cell subsets are CD56bright and CD56dim subsets. Of these, the CD56dim subset predominates, and these are typically ~90% of peripheral blood NK cells in healthy individuals13. CD56dim NK cells are often referred to as the most inherently cytotoxic subset as they express lytic granule components and certain activating receptors at baseline, whereas the CD56bright subset is described as poised for cytokine production14. However, both subsets can be rapidly induced to perform the functions ascribed to the other under activating conditions15–20.
In addition to CD56bright and CD56dim NK cell subsets, there are other subsets of NK cells defined by their functional and phenotypic characteristics that can be found in peripheral blood. These include circulating NK/ILC precursors (ILCP) and CD34+ precursors that give rise to NK cells in vitro or in humanized mouse models21–23. Peripheral blood is also a source of adaptive, memory, or memory-like NK cells (described in more detail below), and subsets that are considered transitional between CD56bright and CD56dim24, 25. In addition, a minor CD56negative NK cell subset is present in peripheral blood that is expanded during certain chronic viral infections. This population was first found in individuals with HIV and hepatitis C virus (reviewed in26 and more recently also described in individuals with Burkitt lymphoma and those co-infected with cytomegalovirus and Epstein-Barr virus (EBV)27, 28.
Certain tissues, particularly secondary lymphoid tissue, are sites of NK cell development and the common paradigm is that precursors undergo maturation in tissue and then enter circulation as mature NK cells (NK cell development is discussed further below). Therefore, subsets of NK cells found in tissue can also represent distinct stages of an ongoing process of differentiation. That said, there are also specialized tissue resident NK cell subsets in tissues including uterus, lung, liver, and lymph node, that carry out immunoregulatory functions 12, 29–32. Phenotypic identifiers of tissue resident NK cells are frequently those that are also found on T cells and include CD103, CD49a, and CD6912, 31–33.
Finally, even routine immunophenotyping of NK cells can be complex. When considering the phenotype of NK cells in peripheral blood, the most accessible site of human NK cells, the commonly used definition of NK cells is CD56+CD3− lymphocytes. While this definition distinguishes NK cells from CD3+ invariant T cell subsets in peripheral blood, it should also be noted that CD56 is expressed on certain myeloid cells34, a subset of ILC/NK precursors23, and ILC335. While these cells are rare in circulation, they are present in tissue and the definition of canonical NK cells to the exclusion of other subsets in tissue, and ideally in peripheral blood, requires additional markers. Some clinical phenotyping laboratories use a combined CD56 and CD16 antibody cocktail to identify NK cells in peripheral blood36, which prevents discrimination between CD56bright and CD56dim subsets. As distinction of these subsets can be informative for identifying NK cell deficiency or dysregulation (see discussion of primary immunodeficiencies below), a more informative flow cytometry panel for clinical use includes separate immunostaining for CD56 and CD16 and may include other parameters such as CD57 to distinguish terminally mature NK cell subsets, and perforin/granzymes as a measurement of functional capacity37.
Human NK cell development and homeostasis
Bone marrow is frequently cited as the site of NK cell differentiation as a spectrum of NK cell developmental intermediates from the earliest precursor to mature cells can be identified in human bone marrow33, 38–42. However, defining the stages of NK cell development based on the phenotype and lineage potential of NK cell precursors has demonstrated that there are other tissues that can support the generation of NK cells from early bone marrow-derived precursors that likely enter circulation and seed peripheral tissue. The best described of these sites is secondary lymphoid tissue, particularly tonsil,32, 33, 43–46 but decidua, liver, intestine, and thymus can also seemingly host a continuum of NK cell development from common lymphoid progenitor-like cells 47–52. These sites and others, such as lung, are also home to tissue resident NK cells that can also likely be generated from more developmentally restricted circulating NK/ILC precursors22, 29, 31–33, including the generation of tissue resident cells with adaptive properties53.
Human NK cell development has been extensively reviewed elsewhere40, 44, 46, 54–56 but is briefly summarized here. While NK cell differentiation can be classified in different ways and is still being defined particularly in the context of development of other ILC subsets, it can be broadly classified in 3 stages: commitment to a lymphoid lineage, commitment to an NK/ILC lineage, and commitment to the conventional NK cell lineage (Figure 1). NK cells arise from bone marrow-derived CD34+ hematopoietic progenitors and undergo differentiation that can be defined phenotypically by cell surface receptor and transcription factor expression, and functionally by changes in lineage potential45, 46, 54, 57. Early stages of NK cell development in the tonsil begin with a CD34+CD38−CD45RA+CD10+CD7+CD117−CD94−CD16− common lymphoid progenitor-like cell that also has the capacity for dendritic cell and T cell generation. This multipotent progenitor then differentiates to a more restricted precursor with NK or NK/ILC lineage potential (ILCP) that can also be detected in circulation, suggesting that it is a developmental intermediate that can seed peripheral tissues for further differentiation22, 23, 43. Commitment to a conventional NK cell lineage from an NKP/ILCP lineage is marked by further NK cell lineage progression to CD117+/−CD94+CD16− CD56bright NK cells, and ultimately, CD117−CD94+/−CD16+ CD56dim lytic effector NK cells that predominate in circulation and can be a source of adaptive NK cells following viral or cytokine challenge44, 46, 55 (Figure 1). While investigations into the identity and plasticity of NK/ILC precursors is ongoing, true commitment to a functionally mature NK cell lineage at the exclusion of all other subsets likely occurs at the CD56bright stage, specifically with the acquisition of NKp80 by a Lin−CD34−CD117+/−CD94+CD16− CD56bright NK cell58. Ultimately, these studies underscore the plasticity of innate lymphoid precursors and the role that interactions with microenvironmental signals play in their fate specification.
Figure 1. Simplified scheme of human NK cell development.
Hematopoietic stem cells (HSC) give rise to common lymphoid progenitor (CLP)-like precursors that can seed peripheral tissue and undergo linear differentiation to mature NK cells. NK cell/ILC developmental intermediate precursors (NKP/ILCP) can be found in circulation and in tissue and can give rise to other ILC subsets or conventional NK cells. Commitment to conventional NK cell lineage is thought to be marked by acquisition of NKp80 followed by further maturation to CD56dim lytic effector cells that are predominant in circulation. Tissue resident NK cells have a unique and have a distinct phenotype but their direct precursor is unclear and it is unknown if they circulate (indicated with dashed arrows); some tissue resident NK cells can also adopt an adaptive phenotype. Made with Biorender.
In addition to the identity of NK and ILC precursors, other fundamental questions about NK cell development and homeostasis remain unanswered. These questions include the physiological significance of the generation of NK cells from myeloid precursors59, 60, and, perhaps most strikingly, the true nature of the relationship between CD56bright and CD56dim NK cell subsets in peripheral blood. Early evidence suggesting CD56bright cells were a precursor of CD56dim cells included longer telomeres in CD56bright cells61, their appearance in circulation before CD56dim cells following transplant62, subsets of NK cells with intermediate properties between CD56bright and CD56dim subsets24, 25, and studies in humanized mice showing that adoptive transfer of CD56bright cells leads to production of CD56dim cells23, 63. More recently, scRNA-Seq studies have identified a trajectory of development that similarly places CD56bright cells as the precursors of the CD56dim subset41, 64. These studies have been countered by studies from non-human primates that suggest the two subsets may have distinct origins65. In addition, the relatively low frequency of NK cell precursors and subsets has made it difficult to robustly construct NK cell developmental trajectories from scRNA-Seq data66. Ultimately, the fundamental difficulties in recapitulating human NK cell development using in vitro systems or mouse models have made it difficult to mechanistically dissect this process.
Finally, our evolving understanding of other innate lymphoid cell subsets continues to challenge our understanding of the function and etiology of human natural killer cells. Bona fide NK cells are often identified by their unique ability to perform perforin and granzyme-based cytotoxicity, however other immunoregulatory functions can be shared with other ILC subsets67, 68 and the recent description of cytotoxic ILC subsets further confounds this definition69, 70. The phenotypic similarities between particularly NK cell developmental intermediates and group 3 ILCs35, 71, combined with the known lineage plasticity between NK cells and ILCs72, 73, suggests that caution should be taken when identifying particularly tissue resident NK cells but also circulating NK and ILC subsets.
NK cell effector functions
Immune synapse formation
Cytotoxic effector function of NK cells is mediated by the formation of an immunological synapse which promotes directed secretion to effectively lyse target cells and minimize bystander effects of toxic lytic granules. While NK cells use diverse activating receptors to initiate their function, many signaling pathways are common to those mediated by T cell receptor signaling, and the fundamental steps of cytotoxicity, including lytic granule convergence to the microtubule organizing center (MTOC), actin remodeling, lytic granule polarization to the synapse, and granule exocytosis, are executed in both cytotoxic T lymphocytes and NK cells 74. Despite these structural similarities between NK cell and cytotoxic T lymphocyte (CTL) cytolytic synapses, there are also differences between them, particularly in the kinetics of target cell killing and effector cell activation. As T cell mediated recognition of targets is antigen specific and T cell receptor (TCR)-mediated signaling is rapid and robust, it is thought that NK cells pass through more ‘checkpoints’ prior to fully committing to lytic function, and the time taken to full NK cell activation is longer than that of T cells75, 76. This may be related to relative strength of signaling, as stronger TCR signaling correlates with more rapid immune synapse formation in CTLs77–79 and the inherent balance between activating and inhibitory receptor signaling in NK cells means that NK cells may engage in an immune synapse in the presence of inhibitory signaling. In contrast to activating receptors, engagement of inhibitory NK cell receptors leads to dephosphorylation of signaling intermediates such as Vav1 by phosphatases including SHP-180, 81. Following initial cell contact and subsequent inhibitory receptor ligation, formation of the immune synapse is terminated, and the NK cell disengages5, 82.
NK cells can function as ‘serial killers’, and single NK cells can mediate killing of multiple target cells83–88. Typically, this number has been defined as 3–4 target cells, however there is significant, poorly understood heterogeneity in the capacity of freshly isolated human NK cells to mediate serial killing, and this heterogeneity is likely related to cellular fitness, including NK cell education89. In addition, the modalities of NK cell killing can change over the course of several kills, with initial events often being granzyme B mediated, and then switching to death receptor-mediated killing at later time points85. Better understanding how NK cell function can be maintained over the course of multiple target cell kills is of interest for the use of NK cells as therapeutic tools in the fight against solid tumors.
Finally, while many studies of NK cell immune synapse formation have been performed in isolated or 2D environments, the microenvironments in which NK cells exert their function are complex and multidimensional. Studies of immune synapse formation are often predicated on the presence of a single target cell, whereas in complex environments multiple susceptible targets may be in contact with an NK cell at a given time. There is evidence that NK cells can exert serial killer function by repolarizing towards multiple targets sequentially90, 91. However, they can also exert multi-directional signaling that may be more efficacious in a crowded tumor microenvironment92.
Death receptors.
In addition to perforin- and granzyme-dependent mechanisms, NK cells also kill via contact-dependent Fas-FasL and TRAIL mediated interactions, which activate death receptors CD95/Fas and TRAIL-R1-R2 on target cells respectively and lead to caspase-dependent apoptotic signaling in the target cell (reviewed in93, 94). While the contexts in which NK cells utilize this form of killing are not completely understood, death receptor signaling occurs across longer time scales and is preferentially utilized by certain NK cell subsets95, or NK cells performing multiple target cell kills that have already executed perforin-dependent killing85.
NK cell cytokine secretion
NK cells are important producers of cytokines, particularly IFNγ, which plays an important role in promoting host defense against intracellular pathogens and tumorigenic cells96. NK cell mediated cytokine production can activate innate and adaptive immune cells through the recruitment of cells to the site of infection, the upregulation of MHC molecules to help facilitate T cell recognition, and the promotion of Th1 differentiation. In addition, NK cells secrete TNFα and other pro-inflammatory cytokines, and IL-10, which is more immunomodulatory. Cytokine secretion by NK cells is induced by the same pathways of activation that promote target cell killing, namely engagement of activating receptors, including CD16 (FcγRIIIA)8. In addition, NK cell cytokine secretion can be induced by activation with other cytokines including IL-1, IL-2, IL-12, IL-15 and IL-188. Relative to immune synapse formation, which has been extensively studied in NK cells, the mechanisms of cytokine secretion are less well described. However, while perforin-containing lytic granules are secreted directionally at the immune synapse, cytokines can be secreted non-directionally and are trafficked through distinct pathways from that of lytic granules97. As with lytic granule secretion however, at least some IFNγ secretion is released by directed secretion at the immune synapse, at least in response to NKG2D ligation, and is regulated by similar properties of immune synapse function that dictate lytic granule release98. In the case of both cytokines and lytic granules this likely reflects the role and importance for directed vs. non-directed secretion, where the former serves to selectively eliminate certain target cells and the latter to activate the immune response rapidly and broadly.
NK cell activation, inhibition, and licensing
The classical model for NK cell activation is described by the ‘missing self hypothesis’99, 100. This framework first accounted for the observation that NK cells can lyse targets without prior sensitization by predicting that the downregulation of MHC class I molecules made target cells susceptible to NK cell mediated lysis by failing to provide a ligand for NK cell inhibitory receptors101. These inhibitory receptors, and subsequently their activating counterparts, were later described to be killer immunoglobulin-like receptors (KIRs) and CD94/NKG2A102. This model has served as a foundation for our current interpretation of NK cell function that has been expanded to include the responsiveness of NK cells to upregulated activating ligands on stressed or virally infected cells103, the recognition of viral peptides in the context of nonclassical MHC I molecules104–106, and the generation of adaptive or memory-like NK cells in response to specific activating conditions (reviewed in107). Our understanding of the function of KIR molecules has been further informed by the in-depth study of how different KIR haplotypes and their recognition of MHC I affect NK cell function, particularly in settings of HIV/AIDS and transplantation. Finally, the role of KIRs in tuning NK cell function in response to the presence of self-ligand has been further illuminated by studies of NK cell education, or licensing, in which NK cell functional capacity is granted upon ligation of inhibitory KIRs with cognate self receptors. This process of NK cell education is not fixed, and instead can be viewed as a tunable response that can likely help adjust the threshold of NK cell activating responses in a variety of settings.
NK cell activating receptors
In addition to KIRs, which help discern self from non-self through MHC I recognition, there are a host of NK cell receptors that have evolved to help recognize virally encoded ligands or molecules that are upregulated on stressed or infected cells. Generally, NK cell activation is thought to require more than one activating signal, with a second co-stimulatory signal often arising from integrin ligation108. The exception to this paradigm is CD16, as CD16 ligation is sufficient to cause NK cell degranulation in the absence of other signals108. A brief summary of key NK cell activating and inhibitory receptors is provided below.
Activating KIRs.
KIR repertoires are highly diverse due to allelic polymorphisms, the presence or absence of individual genes, and gene copy number109, 110. KIR nomenclature reflects their function, with the 2 characters following KIR (ie 2D or 3D) referring to the number of extracellular domains and the letter S or L referring to short (activating) or long (inhibitory) intracellular domains109. The KIR gene cluster is located on chromosome 19, and KIR haplotypes referred to as ‘A’ or ‘B’ are classified based on their gene content dictated by position and the presence of recombination hot spots, and these haplotypes have relevance particularly to transplantation as they differ in their content of activating KIRs111.
KIR ligands are classical or non-classical MHC I, with different KIR having affinities for different HLA allotypes112. While inhibitory KIRs contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) domain in their intracellular domains, activating KIRs are paired with the immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor DAP12 to mediate activating functions (reviewed in113). This utilization of the ITAM motif aligns KIR-mediated activating signaling with other ITAM-based signaling, such as signaling through CD3ζ, whereas ITIM-mediated inhibitory signaling recruits phosphatases SHP-1 and SHP-2 to repress activating signaling cascades114. In this way, the variegated expression of activating and inhibitory KIR is thought to represent a balance of signaling that can be tipped in favor of activation in the presence of sufficient activating ligand103. This balance can also be considered in the context of education or licensing, which refers to the ligation of inhibitory receptors, either KIR or CD94/NKG2A, that leads to enabling NK cells for function (reviewed in115). While the nature and implications of KIR genetics are complex, this fundamental understanding can help inform thinking of their importance, particularly when considering HLA genetics in transplantation.
Natural cytotoxicity receptors (NCRs).
In addition to KIRs, NK cells express natural cytotoxicity receptors including NKp30, NKp44, and NKp46. As opposed to KIRs, these are not MHC restricted and instead bind host or pathogen encoded ligands, making them poised to mediate the frontline response to viral infection or emerging malignancy (reviewed in116). Like activating KIRs, NCRs lack intrinsic activating function but instead pair with ITAM-bearing adaptors including DAP12 (NKp44)117–119, or CD3ζ or FcεRIγ (NKp46, NKp30)120, 121 to mediate activating signaling leading to lytic function or cytokine secretion122. In addition, NKp44 and NKp30 can mediate inhibitory functions in response to certain ligands123–126. However, the primary function of NCRs is thought to be activation, and each receptor can bind a wide array of ligands, including viral hemagglutinins encoded by influenza and vaccinia viruses116.
NKG2D.
NKG2D is a type II transmembrane receptor that, in humans, is expressed solely as the NKG2D-L isoform and pairs exclusively with the YINM activating motif-containing DAP10 adaptor127–129. NKG2D ligands include MICA, MICB, and ULBPs, which are ligands associated with stress, infection, and inflammation130. NKG2D-mediated signaling through DAP10 association leads to activation of Vav1 and phosphatidylinositol-3-kinase and ultimately the actin remodeling and calcium flux that promote lytic granule exocytosis at the immunological synapse131.
FCγRIIIA.
NK cells express CD16a, the low affinity FcγRIIIA receptor that induces antibody-dependent cellular cytotoxicity, thus making CD16-mediated function an important component of monoclonal antibody-mediated immune therapies132. Human CD16 exerts strong activating signaling by pairing with homo- or heterodimers of ITAM-domain containing FcεRIγ and CD3ζ adaptors and is thought to be the only activating receptor that can trigger degranulation without a co-stimulatory signal103, 108, 133, 134. Cleavage of CD16 from the cell surface by ADAM metalloproteases following activation helps to limit its function and likely prevent autoinflammation, but also acts as a mechanism to facilitate NK cell detachment from targets and promote serial killing135, 136. There are additional variables that can affect CD16 function, including post-translational modifications and single nucleotide polymorphisms137–140. In addition, engineering of a non-cleavable form of CD16 for CAR-NK therapy has demonstrated that limiting activation-induced cleavage can further potentiate CD16-mediated cytotoxicity when directed via bispecific engagers141–143.
2B4/CD244.
2B4 is a member of the signaling lymphocytic activation molecule (SLAM) family of receptors, which encode immunoreceptor tyrosine-based switch motifs (ITSM) that promote their association with adaptors SLAM-associated protein (SAP), Ewing’s sarcoma associated transcript 2 (EAT2), and EAT2-related transducer (ERT), and the phosphatases SHP-1 and −2 and SHIP-1144–149. SAP recruits Fyn, which activates tyrosine kinase signaling cascades that converge on downstream signaling for cytotoxicity. The ligand for 2B4 is CD48, another SLAM family receptor that is upregulated on virally infected cells, particularly EBV infected cells150. 2B4 can also help mediate lysis of HIV-infected CD4 T cells151. NK cells from SAP-deficient patients are impaired in their ability to lyse virally infected target cells144, 152–155, and patients with X-linked lymphoproliferative disease due to damaging SAP variants present with severe and often fatal EBV, suggesting that impaired NK cell activation contributes to this clinical phenotype156. While SLAM family receptors are largely activating when paired with SAP adaptors, in the absence of SAP expression they exert inhibitory signaling by pairing instead with inhibitory phosphatases144–147.
NKG2C.
NKG2C forms an obligate heterodimer with CD94 and binds to the non-classical MHC I molecule HLA-E157, 158. In addition to its role as an activating receptor that signals through DAP12 to activate cytotoxic functions159, expansion of NKG2C+ adaptive cells occurs in response to viral infections including cytomegalovirus160–165 and Hantavirus164. While the observation that NKG2C+ cells selectively expanded in certain individuals following viral infection was made many years ago, the mechanism of this expansion was recently described to be the selective stabilization of HLA-E when bound to specific viral peptides. This, combined with cytokine signaling, leads to selective expansion of NK cell subsets that are then primed for future re-activation as adaptive NK cells104.
DNAM-1.
DNAM-1 is an activating receptor that binds CD155 (poliovirus receptor) and CD112 (nectin-2), which are expressed on virally infected and stressed cells and are also ligands for the inhibitory receptor TIGIT166. DNAM-1 ligation promotes cytotoxicity and helps to stabilize LFA-1 to facilitate adhesion at the immune synapse167, 168. Phosphorylation of DNAM leads to recruitment of Grb2 and activation of Vav1, PI3K and PLCγ, thus directly activating NK cells for cytotoxic function169. DNAM-1 can also synergize with 2B4, suggesting a direct and co-stimulatory role in both activating signaling the generation of adaptive NK cells170.
Integrins and other adhesion molecules with co-stimulatory function
While they do not have inherent cell activation properties, integrins are often considered a co-stimulatory molecule for NK cell cytotoxicity108, and NK cells from individuals with leukocyte adhesion deficiency-1 resulting from damaging LFA-1 variants have impaired NK cell cytotoxic function171–176. Consistent with integrins’ known function in mediating cell adhesion, their co-stimulatory function at the synapse is exerted by enhancing adhesion to ICAM-1+ target cells and promoting actin remodeling for firm adhesion. Integrin ligation also provides an early signal for lytic granule convergence that is an early step in NK cell cytotoxicity and promotes directed secretion103, 171, 177. In addition to roles in promoting target cell interactions, integrins play an important role in cell trafficking and cell migration, and NK cells express a host of integrins that mediate these processes (reviewed in178). As is the case with other immune cell subsets, integrins such as CD103 and CD49a are also associated with NK cell tissue residency31. Finally, the glycoprotein CD2, which binds to LFA-3, acts as a co-stimulatory molecule on NK cells. CD2 function is exerted in part through stabilization of CD16 at the immune synapse and by amplifying signaling through CD3ζ in synergy with activating receptors including CD16 and NKp46179–181.
NK cell inhibitory receptors
NK cell inhibitory receptors, including inhibitory KIRs and NKG2A, play an important role in the restraint of autoimmunity by sparing self MHC I-expressing cells from NK cell mediated lysis. More recently a role for checkpoint inhibitory receptors in NK cell function has been debated and other non-canonical inhibitory receptors have also been described in greater detail.
An additional important role for inhibitory receptors is through their licensing of NK cell function. Given their heterogeneous expression of activating and inhibitory receptors and potent expression of lytic effector molecules, NK cells have potential for self-reactivity. NK cell licensing, arming, and education refer to processes by which an NK cell only gains full functional capacity if an inhibitory receptor, such as inhibitory KIR, NKG2A, or LILRB-1, is engaged with cognate self ligand (reviewed in182). While this is an intuitive failsafe, the cellular mechanisms of education, licensing and arming/disarming are still not completely understood. Education leads to increased lytic granule size and NK cell functional capacity89 and disarming leads to increased expression of SHP-1, suggesting that ITIM-mediated signaling can function in restraining uneducated cells183. Notably, however, these responses are tunable, and transplant of NK cells can lead to “re-education” in a new host184–188. In addition, there is likely a functional role for uneducated, unlicensed, or unarmed cells, which are not eliminated, retain functional capacity, and may make up as much as 25% of an individual’s NK cell population189–191.
Inhibitory KIR.
Inhibitory signaling by KIRs is ITIM-mediated through the recruitment of phosphatases including SHP-1 and SHIP-1 that act on proximal kinase signaling such as Vav1 and the adaptor protein Crk80, 192, 193. As such, inhibitory receptor signaling in the absence of robust activation signaling can rapidly disarm a potential lytic interaction and leads to dissolution of the immunological synapse and disengagement of the NK cell from its target5, 82, 194, 195. This negative regulation is exerted at the molecular level, including through the clustering of inhibitory KIR in response to activating receptor ligation196, 197. This mobilization of inhibitory signaling machinery even in response to activating signals suggests that nanoscale receptor organization on the cell membrane functions to modulate NK cell activating thresholds.
NKG2A.
NKG2A is expressed as an obligate heterodimer with CD94, and its expression is associated with immature NK cell subsets as it is expressed prior to KIR receptors during NK cell differentiation157, 198. As such, CD94/NKG2A can also participate in NK cell licensing in the absence of KIRs through ligation of HLA-E and this process may be particularly important in uterine NK cells199, 200. The high expression of HLA-E in solid tumor settings has made blockade of NKG2A-HLA-E interactions a target of interest for immune therapeutic approaches201, 202.
LILRB-1.
While less studied that inhibitory KIR, LILRB-1 (LIR-1, ILT-2, CD58j) binds classical and non-classical MHC-I molecules in addition to UL-18 expressed on CMV infected cells203, 204. LIR-1 expression is associated with the acquisition of NK cell memory in response to CMV, and LIR-1 engagement with cognate MHC-I can mediate NK cell education205.
Checkpoint proteins.
The role of the checkpoint molecule PD-1 in human NK cell function has been debated206, however both direct and indirect evidence for PD-1 expression and function on NK cells in the context of viral infection and malignancy has been reported (reviewed in207). Other checkpoint molecules can also play a role in NK cell function. TIGIT, an inhibitory receptor that binds DNAM-1 ligands CD155 and CD112, is induced on NK cells following tumor cell co-culture and blocking TIGIT ligation enhances the NK cell mediated antitumor response208–210. Human NK cells also express TIM3, which is of interest for its role in promoting solid tumor clearance by NK cells211, 212.
Siglecs.
Siglecs are sialic acid binding immunoglobulin-type lectins which bind to glycans on the surface of target cells213. They contain ITIM motifs and, as such, execute inhibitory signaling in the same way as inhibitory KIRs. NK cells express Siglec7, which bindsα2–8 sialic acid, and Siglec-9, which bindsα2–3 sialic acid. Siglec-7 is uniformly expressed on human NK cells214, 215, whereas Siglec-9 is expressed on a subset of CD56dim NK cells216. In addition to binding glycans on target cells in trans, Siglecs can be modulated by interactions in cis, and removal of sialic acid, but not polysialic acid, on NK cells by neuraminidase increases NK cell cytotoxicity by de-inhibiting Siglec-7217.
Memory, memory-like, and adaptive NK cells
While NK cells do not possess antigen-specific receptors generated by genetic rearrangement, they can exert immunological memory as defined by the classical definition of a population of cells that expands, contracts, and then is primed for further function in response to a specific activation signal (reviewed in107). The first evidence of NK cell memory was generated in murine models of hapten sensitization218, 219 and the identification of specificity of the murine receptor Ly49H for the m157 CMV viral peptide220, 221. Subsequently, the presence of memory NK cells circulating in humans with prior CMV exposure led to the observation that multiple viral infections can generate NK cell subsets that are long-lived and primed for subsequent re-exposure160–165. This subset is often defined as being NKG2C+, however other phenotypes of adaptive NK cells have been described222, 223, and adaptive NK cells are present in individuals who do not express NKG2C179, 224. Notably, similar adaptive NK cell phenotypes can also be generated by cytokine exposure leading to cytokine-induced memory-like (CIML) NK cells, suggesting that in addition to receptor-ligand mediated activation, NK cells can ‘remember’ certain cytokine contexts that prime them for re-activation225–227. The generation of cytokine-induced memory like cells that have enhanced effector function and survival is of particular interest to the field of NK cell adoptive therapies.
Great progress has been made in recent years in the understanding of mechanisms of NK cell memory, and it is now recognized that this process includes epigenetic and genetic responses and remodeling of metabolic programming to enable enhanced recall function222, 228, 229. In addition, the mechanism of CMV generation of NK cell memory was recently elucidated by the finding that specific CMV viral peptides bind and stabilize HLA-E to generate adaptive NK cells104, thus partially solving the mystery of how viral peptide could be recognized in the absence of antigen receptor rearrangement. While CIML cells share the core hallmarks of immune memory with hapten-induced or virus-induced memory cells, CIML cells uniquely have enhanced recall function to multiple stimuli after their generation227, 230. Ultimately, the mechanisms of the generation of each NK cell memory program are distinct in their activation signaling and functional impact230.
Defining the clinical relevance of NK cells
As innate effector cells, ultimately NK cells are poised to provide a first line of immune defense, and their function reflects this purpose. While isolated NK cell deficiencies are rare, mouse models of NK cell depletion and studies of patients selectively lacking NK cells illustrate their critical role in the control of viral infections, particularly herpesviral infections231–233. While there has been debate about the redundancy of innate lymphoid cells in human health234–236, there are specific contexts where NK cells have been demonstrated to be particularly important for clinical outcomes. These include hematopoietic stem cell and bone marrow transplantation, clinical outcomes from solid tumor settings, and primary immunodeficiencies that reveal the consequences of aberrant NK cell function.
The discovery that KIR-mismatched grafts for treatment of leukemia could help prevent relapse in the absence of graft versus host disease provided evidence of the clinical relevance of the missing self hypothesis and generated excitement about the role that NK cells could play in allogeneic transplant237. Since then, the importance of KIR and HLA gene haplotypes in determining the outcome of allogeneic transplants has been further elucidated and demonstrated to be of importance. Specifically, the presence of a KIR B haplotype, which includes activating KIR, is associated with better outcomes and relapse protection. This finding was recently revisited in the context of reduced intensity conditioning and better HLA matching and found to be robust238.
Primary immunodeficiencies and NK cells
There were more than 50 single gene defects that cause an NK cell phenotype reported in the 2019 International Union of Immune Societies report239–241. In contrast, there are only 6 genes in which damaging variants are known to cause isolated NK cell deficiency through impaired generation or development of NK cells, and only one that causes selective NK cell deficiency through impairment of function (reviewed in 241). Further, several of the genes that cause developmental NKD do so only in the context of specific variants or unknown environmental contexts, including GATA2 deficiency242–248 and RTEL1 deficiency249, 250. As such, it has been difficult to evaluate the functional importance of NK cells in the absence of perturbations to other immune cell compartments. New insight into this question was recently provided in the case of an individual with severe combined immune deficiency caused by IL2RG mutation and reversion variants in a lymphocyte precursor that restored T cells but not NK cells233. The continued absence of NK cells in his peripheral blood, and the accompanying NK cell dysfunction, was paired with severe, recalcitrant cutaneous HPV infection. This is perhaps the most clearcut context for selective loss of NK cells, and one that underscores the true importance of NK cells particularly in controlling herpesviral infections.
Developmental NKD
While certain gene variants that cause severe combined immune deficiency also impair NK cell development, such as IL2RG deficiency, it is notable that there has been no NKD to date that reports a singular ‘hard stop’ in NK cell development while sparing other lymphocyte lineages such as T cells. This observation likely reflects both the shared lineage and function of NK cells with other immune cell subsets and the lack of positive or negative selection events, analogous to positive and negative selection, that prevent the differentiation of dysfunctional T and B cells. Several NKD have been described as leading to blockade in NK cell terminal maturation as defined by the relative under-representation of the CD56dim subset in peripheral blood. These are reviewed elsewhere241, but it should be noted that these frequently affect genes involved in cell cycle and DNA damage, including CDC45-MCM-GINS (CMG) helicase components MCM4251, 252, MCM10253, 254, and GINS1255. These are accompanied by other reports of NK cell deficiency in an RTEL1 deficient patient249, 250, and in POLE1 and POLA1 deficiencies256, 257, suggesting a link between proteins involved in cell cycle, genomic stability, and DNA replication and NK cell deficiency. Together, these cases suggest that NK cells have a unique vulnerability to variants that affect cell cycle progression or the DNA damage pathway, however the reason for this susceptibility is not clear. Further, the peripheral blood phenotype of decreased CD56dim cells is not absolute and could represent other conditions such as the impaired survival or homeostasis, as opposed to generation, of certain NK cell subsets. This was described to be the case for GATA2 deficiency, where the depleted CD56bright subset in GATA2 patients reflects the selective survival of long-lived adaptive cells that have a CD56dim phenotype246. Similarly, the unexplained NK cell phenotype of over-represented CD56bright cells in the peripheral blood of patients with congenital neutropenia may be related to differential homeostasis of the CD56bright and CD56dim subsets, as opposed to a bona fide ‘block’ in NK cell development258, 259. Here again, the difficulties in modeling specifically human NK cell homeostasis and development have made even these fundamental questions difficult to answer.
Functional NKD
Due to the similarities in the mechanisms of lytic function between NK cells and cytotoxic T lymphocytes, there in only one known gene variant that selectively impairs NK cell cytolytic killing. Many genes associated with defective CTL function, such as those related to exocytosis, activation, and actin remodeling, similarly affect NK cell function. One exception is FCGR3A, the CD16 Fc receptor that is expressed on NK cells and mediates ADCC. While damaging variants in CD16 have been reported, surprisingly the L66H variant (also reported as L48H) did not impact ADCC, but instead decreased the capacity of NK cells for killing of MHC class I deficient targets through the destabilization of the co-stimulatory receptor CD2181, 260, 261. This finding both revealed an unexpected role for CD16-CD2 interactions and underscored the importance of CD2 function given the significant viral susceptibility of patients with this variant. While full understanding of the transmembrane interactions between CD16 and CD2 is still lacking, the L66H variant causes structural changes in CD16 that lead to loss of detection of CD16 by the B73.1 monoclonal antibody but does not affect detection by the 3G8 monoclonal antibody. This differential binding provides a simple way to screen for this variant, although it should be noted that not all loss of B73.1 detection is associated with this damaging variant, and in some cases NK cell deficiency is not associated with the phenotype of loss of detection by B73.1 or even the presence of an L66H variant, which in some patients does not appear to directly affect NK cell function261–263.
Advances in therapeutic uses of NK cells
Several properties of NK cells make them attractive as tools for immune therapy. These include lytic effector function that is not HLA-restricted and the limited risk of graft versus host disease relative to T cell therapies. Current approaches for NK cell therapy include the modification of NK cells with engineered receptors and the expansion of NK cells or NK cell subsets for adoptive transfer, and these are briefly described below.
CAR NK cells and bispecific engagers
Like T cells, NK cells can be modified with receptors that target tumor antigens to direct lytic function towards transformed cells. Current CAR-NK products in clinical trial include B cell malignancy targets, myeloid malignancies, multiple myeloma, and HER2-specific CAR for glioblastoma (reviewed in264). Initial results in patients for CAR-NK cells in the treatment of CD19+ B cell malignancies has been highly promising265. Alternatives to CAR engineering include bispecific or trispecific engagers (BiKEs and TriKEs) that combine the targeting of a tumor antigen with cross-linking and activation of NK cell receptors, most frequently CD16, using single variable portions of antibodies266. The small size and direct ligand binding properties of BiKES and TriKES have also made them very promising in pre-clinical testing142, 267, 268.
NK cell expansion and adoptive transfer
NK cell adoptive transfer is often supported by either ex vivo priming, as in the case of CIML NK cells, or in vivo NK cell expansion with administration of IL-2 or IL-15230, 269, 270. The adoptive transfer of CIML NK cells has been demonstrated to lead to notable in vivo expansion and holds tremendous promise particularly for the treatment of relapsed acute lymphoblastic leukemia following hematopoietic cell transplantation227, 271–273. While systemic IL-2 administration has been successful in some contexts, including for therapeutic treatment of Wiskott-Aldrich syndrome274, IL-15 receptor agonists have been favored over IL-2 administration for NK cell adoptive therapy approaches, in part due to the propensity for IL-2 to also expand host regulatory T cells275, 276. N-803 (formerly ALT-803) has been used with haploidentical NK cell adoptive therapy following lymphodepletion for treatment of relapsed/refractory AML and has proved beneficial277. However, the administration of N-803 also promotes recipient T cell activation leading to clearance of donor NK cells and shortening the window of clinical efficacy of NK cell-mediated anti-tumor response278. Ongoing careful study of the benefits and drawbacks of local and systemic cytokine administration will be critical for exploiting the clinical potential of NK cells. Finally, the relative ease of production of NK cells from induced pluripotent stem cells, and the potential for gene editing these, has made iPSC-derived NK cells a promising approach to generate large numbers of effector cells for clinical use279–281.
Ultimately, while NK cell therapies have shown exciting promise in the treatment of hematopoietic malignancies, targeting of immune cells to the site and the immunosuppressive environment in tumors remain substantial barriers to success for NK cell-mediated solid tumor therapies 282. Here again, basic science research aiming to better define the signals that can recruit NK cells to tumor sites and maintain their function will no doubt be informative in continuing to innovate on the existing promising tools in the arsenal.
Concluding remarks
It has been almost 50 years since NK cells were first described as a population of non-T lymphocytes that could eliminate tumor cells without prior sensitization. Since then, investigations into NK cell biology have driven new insight into how viral infections are controlled and eliminated, how tumors are cleared, and how innate and adaptive host defense cooperate in human health and disease. This increasing knowledge has occurred in concert with the emergence of immunotherapies and massive improvements in transplant biology that have further illuminated the clinical importance of innate lymphoid cells. It is hard to predict what the next 50 years will bring, but new single cell analysis approaches are already helping to better understand cellular heterogeneity in many contexts. Together with ongoing improvements in cellular engineering, the future will no doubt hold new clinical applications for innate immune cells and increased understanding of how these cells operate under human physiological conditions.
Figure 2. Simplified scheme of NK cell activating and inhibitory receptors.
A) Commonly expressed NK cell activating receptors, apoptosis-inducing death receptors, and co-stimulatory receptors are shown. Some of these have been shown to play a direct or indirect role in the generation of adaptive NK cell subsets as indicated. B) Commonly expressed inhibitory receptors and checkpoint proteins are shown; some inhibitory receptors also function in NK cell licensing or education as indicated. Made with Biorender.
Summary Box.
Human natural killer cells are innate immune effector cells with demonstrated importance in controlling viral infection and malignancy
Fundamentals of natural killer cell biology include an understanding of their differentiation from precursors, the generation of specialized subsets associated with specific functions or tissue residency, and the mechanisms that control their functions
Natural killer cell dysfunction and impaired differentiation can occur in the context of inborn errors of immunity
Natural killer cells are a promising tool for immunotherapy
Acknowledgments
I thank Dr. Bethany Mundy-Bosse for critical reading of the manuscript. Work in my laboratory is supported by NIH-NIAID (R01AI137073, R01AI137275). Figures were made using Biorender.com.
Footnotes
Conflict of interest: The author has nothing to disclose.
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