A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight, Brendon D

A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight, Brendon D. Parsons, Mir Munir A. Rahim and Andrew P. Makrigiannis This information is current as of September 29, 2021. J Immunol 2020; 204:2867-2875; ; doi: 10.4049/jimmunol.2000196 http://www.jimmunol.org/content/204/11/2867 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight,* Brendon D. Parsons,† Mir Munir A. Rahim,‡ and Andrew P. Makrigiannis† In the past decade, the study of NK cells was trans- immune response could come online. It was a great surprise, formed by the discovery of three ways these “innate” then, when evidence was presented that showed NK cells immune cells display adaptive immune behavior, in- displaying adaptive, T cell–like behavior. The first reports cluding the ability to form long-lasting, Ag-specific showed that NK cells could develop Ag-specific memories in memories of a wide variety of immunogens. In this the absence of T and B cells (which until then were believed review, we examine these types of NK cell memory, to be the sole Ag-specific cells in the immune system) (3). highlighting their unique features and underlying sim- Other reports soon emerged showing that NK cells could ilarities. We explore those similarities in depth, focus- expand in response to CMV, then contract and form a Downloaded from ing on the role that Ly49 receptors play in various memory pool that was more protective on subsequent expo- types of NK cell memory. From this Ly49 dependency, sure (4), or that NK cells could remember a previous acti- we will build a model by which we understand the vation state and respond more rapidly upon future activations three types of NK cell memory as aspects of what is in general (5). Research into these adaptive NK cell responses ultimately the same adaptive immune process, rather soon crystallized into a model that supported three distinct than separate facets of NK cell biology. We hope that a types of NK cell memory (6). For the purposes of this review, http://www.jimmunol.org/ defined model for NK cell memory will empower col- they will be called “adaptive hepatic memory,” “CMV- reactive memory,” and “cytokine-induced memory-like” NK laboration between researchers of these three fields to cell responses (Fig. 1). further our understanding of this surprising and clin- The years since then have allowed more discoveries along ically promising immune response. The Journal of each of these three branches of NK cell memory. Taking Immunology, 2020, 204: 2867–2875. advantage of these new findings, this review will revisit the three types of NK cell memory, highlighting their unique hallmarks, protective capacities, and many similarities. In light atural killer cells are a key component of the innate by guest on September 29, 2021 immune response. These cells employ a broad array of these more recent discoveries, we will then reexamine the N of activating and inhibitory receptors to patrol the three-branched model of NK cell memory to evaluate whether body and detect subtle changes on a potential target cell that it is more appropriate to consider the three types of NK cell might give away a nascent tumor or virus infection. As de- memory as different facets of the same phenomenon or scribed in the missing-self hypothesis, NK cells use inhibitory whether they are truly distinct forms of adaptive immunity. receptors, such as mouse Ly49 or human killer cell Ig-like receptor (KIR) family receptors, to detect levels of proteins The three types of memory associated with health, such as class I MHC (MHC-I) mol- Adaptive hepatic memory. The original discovery of adaptive ecules (1, 2). Cells with normal MHC-I expression engage immune responses mediated by NK cells came from the von these inhibitory receptors and prevent NK cell killing, whereas Andrian laboratory, which reported Ag-specific contact cells that have lost MHC-I (typically indicative of cancer or a hypersensitivity responses against haptens (small chemical virus infection) cannot inhibit the NK cell. In this case, the NK Ags) in mice completely lacking T cells and B cells, which cell is then empowered to both kill the offending cell before a until that moment were understood to be the only adaptive disease can take hold and to release signaling molecules to immune cells (3). These memory NK cells were found orchestrate an entire immune response. uniquely in the liver (3, 7), which was attributed to their Although this missing-self innate immune response makes dependence on the chemokine receptor CXCR6 (8). Mice NK cells a potent first line of defense against tumors and lacking CXCR6 displayed no signs of adaptive NK cell viruses, NK cells were always believed to be just that: cells that memory. Surprisingly, however, blocking CXCR6 or prevented or delayed infection until a more powerful adaptive neutralizing its ligand CXCL16 during the recall response

*Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Address correspondence and reprint requests to Andrew P. Makrigiannis, Dalhousie Boston, MA 02215; †Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. E-mail address: University, Halifax, Nova Scotia B3H 4R2, Canada; and ‡Department of Biomedical [email protected] Sciences, University of Windsor, Windsor, Ontario N9B 3P4, Canada Abbreviations used in this article: CAR, chimeric Ag receptor; DC, dendritic cell; ORCID: 0000-0003-3116-8722 (A.W.). HCMV, human CMV; Ly49C/I, Ly49C and/or Ly49I; MCMV, murine CMV; MHC-I, class I MHC. Received for publication February 20, 2020. Accepted for publication April 6, 2020. This work was supported by a Project Grant from the Canadian Institutes for Health Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 Research (MOP-155906) (to A.P.M.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000196 2868 BRIEF REVIEWS: Ly49 RECEPTORS IN NK CELL MEMORY Downloaded from

FIGURE 1. Overview of the three types of NK cell memory.

in vitro enhanced the NK cell memory response, leading to evidence for NK cell memory in macaques (10), zebrafish the development of a model in which CXCR6 expression (18), and humans (11, 12, 19). http://www.jimmunol.org/ causes memory NK cell homing to the liver but suppresses Unfortunately, how NK cells specifically recognize Ags for NK cell functions in favor of longevity (8). This model has which there is likely no germline-encoded receptor is still more recently been solidified by the Tian laboratory, which unclear. T and B cell populations are able to generate their has demonstrated that IL-7Ra–expressing group 1 innate broad reactivity by random recombination of the T cell or lymphoid cells (which contain NK cells as well as other, BCR genes using the RAG proteins (20). However, this form NK-like innate lymphocytes) initially traffic to the skin- of NK cell memory was specifically discovered in Rag- draining lymph node following hapten sensitization in a deficient animals, meaning that these cells must generate di-

CXCR3-dependent manner (9). These cells gain their memory versity in another manner. Moreover, to our knowledge, no by guest on September 29, 2021 potential in the lymph node, upregulating memory-associated publication to date has described a recombining receptor surface receptors including Ly49 receptors and CXCR6. This within a population of NK cells. Discovering how these NK CXCR6 upregulation along with an increased CD49a cells generate their Ag specificity will likely uncover an en- expression ultimately leads to their liver residence and long- tirely novel process within adaptive immunity, which is what term maintenance through liver-secreted IL-7 (9). Somewhat led our group to explore the possibility that Ly49 receptors paradoxically, studies in primates have not found this liver- are somehow involved in NK cell Ag specificity (21). specific homing, instead identifying NK cells in the liver or The original paper describing adaptive hepatic NK cell spleen that display signs of memory (10, 11). Why different memory found that it is performed by NK cells expressing species have different homing sites for memory NK cells is Ly49C and/or Ly49I (Ly49C/I) (3). Conventionally, Ly49C/I still unknown, but given the many differences between rodent play two roles in NK cell biology. As MHC-I receptors, they and primate NK cells, it is perhaps not surprising. actively participate in the NK cell missing-self response, The von Andrian laboratory later expanded these findings to inhibiting NK cell killing against a target with normal levels include conventional protein-based Ags, showing that various of MHC-I expression as described above (1, 22). As self- inactivated viruses or virus-like particles could provoke Ag- reactive receptors, they also participate in a process known specific allergic responses or even mediate Ag-specific pro- as NK cell education or licensing, by which the NK cell learns tection against lethal infections (8). In particular, they found what a “normal” level of MHC-I is (23–26). Essentially, by that HIV Ags could provoke Ag-specific NK responses in demonstrating an ability to be inhibited through these Ly49 mice, making it unlikely that these responses were the result of receptors, the NK cell is licensed to perform its full range of some germline-encoded receptor for common mouse patho- cytotoxic effector functions. gens. Other groups have subsequently found evidence to Recently, however, another feature of Ly49C/I has been support this diversity in options for NK cell Ag specificity, brought to light. Work from the Kane laboratory has shown finding specific NK cell responses to influenza virus (12), that Ly49C in particular is sensitive to the peptide presented on HSV-2 (13), amoxicillin (14), Salmonella (15), vaccinia (16), the MHC-I it is binding (27). We hypothesized that this and Ebola virus (17). Unlike other forms of NK cell memory, peptide sensitivity might be involved in the Ag specificity of these responses are all Ag specific: for example, NK cells with the NK cell memory response and have recently published enhanced influenza reactivity do not show memory to respi- findings that show adaptive NK cell memory is not merely ratory syncytial virus (12), and HSV-primed cells have no associated with Ly49C/I expression but is actively dependent memory against B16F10 melanoma (13). Although the initial on their expression and activity (21). We show that Ly49C/I findings were performed in mice, these later results provide must be functional, MHC-I must be presenting Ag to elicit The Journal of Immunology 2869

CD16, in contrast to the CMV-reactive memory cells. A more recent paper from the Paust laboratory has identified human NK cells in humanized mouse livers that display adaptive NK cell memory and express CXCR6, Eomes, and CD69 (11). This same study also identified a similar NK cell subset that was recruited to sites of vesicular stomatitis virus challenge in human volunteers and displayed marked inflammation-induced cytotoxicity increases, reminiscent of the above IL-12–induced cytotoxic response. Finally, if Ag specificity is the hallmark of this form of NK cell memory, it raises the question of how Ag is presented to these cells. A publication from the Hornung laboratory took advantage of a unique, NK cell–stimulating hapten to demonstrate that the APC for adaptive NK cell memory is the macrophage, using an inflammasome-dependent mechanism (30). Although this might be a unique property of the hapten used in their study, macrophages are classic examples of good

APCs. Moreover, the inflammasome is a source of potent NK Downloaded from cell–stimulating cytokines like IL-18, making this a plausible model for Ag presentation to memory NK cells. Furthermore, in SIV-infected primates, a robust NK cell infiltration 1 d postinfection correlates with a strong inflammasome gene FIGURE 2. Evidence of the extent of Ag specificity of adaptive hepatic signature (31), and mice lacking inflammatory CCR2+ memory. NK cell memory response to hapten, peptide, or protein Ag challenge monocytes were reported to show no NK cell–mediated http://www.jimmunol.org/ in mice is dependent on Ly49C/I and on prior sensitization with the same or benefit from a Candida albicans vaccine (32), supporting the highly similar Ag. Lack of memory response (indicated by blue line) when mice are challenged with a distinct Ag (blue) versus same or similar Ag (red). All the hypothesis that macrophages, or perhaps all monocyte-derived 2 2 above memory responses were observed in Rag1 / mice, * indicates memory APCs, and the inflammasome play a central role in adaptive 2 2 phenotype observed in CD8a / mice. NK cell memory responses. Our own research into the role of Ly49 receptors in adaptive NK cell memory responses, and the Ag-specific response is NK cell memory has also revealed a feature of how Ags are uniquely sensitive to the Ly49-interacting residues of the presented to memory NK cells. As mentioned above, we found presented Ag (Fig. 2). This Ly49 sensitivity of the Ag-specific that Ly49 receptors were responding to peptides presented on by guest on September 29, 2021 response indicates that Ly49C/I are likely directly involved in MHC-I molecules during an NK cell memory response, and NK cell Ag specificity. Admittedly, we do not preclude the perhaps unsurprisingly, memory NK cells did not respond to possibility of an as-yet-undiscovered receptor’s involvement in Ags presented on MHC class II molecules. However, we were NK cell Ag specificity; indeed, Ly49C/I expression itself is also able to show that whole-protein sensitization with necessary but insufficient to define a memory NK cell, because chicken OVA was able to provoke Ag-specific ear swelling many nonmemory NK cells express Ly49C/I. It is therefore responses when challenged with the OVA-derived SIINFEKL still possible that an Ag-contacting receptor, which confers peptide (a hallmark of adaptive memory) and even mediate MHC-I–restricted Ag specificity to a memory NK cell, will be robust anticancer responses when challenged with OVA- discovered that acts alongside Ly49C/I. However, we have expressing tumors (21). That a whole protein, administered posited a model in which this undiscovered receptor is not exogenously, was capable of sensitizing NK cells to respond to necessary to understand NK cell adaptive responses (21). We MHC-I–presented peptides implies that the APC for NK cell are hopeful that this partial explanation for the memory NK memory is capable of processing and cross-presenting exoge- cell’s Ag specificity will soon lead to a more complete picture nous peptides using MHC-I (Fig. 3). Dendritic cells (DCs), + of adaptive NK cell responses. especially CD8a DCs, are well-known cross-presenters and Beyond this Ly49C/I dependency, there are several other key have a wealth of literature describing their close interactions features of adaptive hepatic NK cell responses. The original with NK cells. Although these interactions have historically discovery of adaptive NK cell memory cells also described them been understood as providing cytokine signals to NK cells, it as expressing Thy1, NKG2D, CD18, and L-selectin, as well as is possible that there has been an as-yet-undetected Ag pre- requiring P/E-selectin for their function (3). Later work ex- sentation event contained within these same DC:NK inter- panded this list to include IFN-g (15, 28), the aryl hydro- actions. This is especially pertinent given that IL-12, IL-15, carbon receptor (AhR) (29), IL-12 (28), and type-I IFNR and IL-18 are produced by DCs when interacting with NK (IFNAR) (28) as required for NK cell memory. In humans, cells (33, 34) and are the key cytokines provoking memory- NK cells with apparent memory activity can be found in the like responses in NK cells, as discussed below. pleural fluid of tuberculosis patients. These cells are CD56+ CMV-reactive memory cells. Around the same time as the 2 CD16 CD45RO+ CXCR3+ NK cells that respond rapidly identification of memory NK cells in mouse livers, evidence to IL-12 by increasing cytotoxicity, CD69, CD25, and was accumulating that CMV infection could shape the NK NKG2D (19). Of particular note is the requirement for cell repertoire (35, 36). This ultimately was recognized as IL-12, which bears a striking resemblance to the cytokine- another form of NK cell memory, based on the relevant NK induced memory-like cells discussed below and the lack of cells undergoing a T cell–like expansion and memory pool 2870 BRIEF REVIEWS: Ly49 RECEPTORS IN NK CELL MEMORY Downloaded from http://www.jimmunol.org/

FIGURE 3. Summary of recent ﬁndings about adaptive NK cell memory and open questions that remain.

2 formation in response to murine CMV (MCMV) (4). Upon CD57+ NKG2A NKG2C+ NK cells (40). They are also challenge, the NK cell population in question would rapidly frequently CD16+ and lack the FceRg1 adaptor protein and expand and clear the virus infection, then undergo a the downstream mediators Syk and Eat-2 (40, 41). This by guest on September 29, 2021 2 2 contraction phase that resulted in a small pool of memory CD16+ FceRg1 phenotype (known as the g NK cell NK cells. Just like their T cell counterparts, these memory phenotype) is significant in a study of NK cell memory, be- NK cells were more reactive upon a subsequent exposure and cause it is associated with extremely potent, mature NK cells would again expand to protect the host. Unlike the hepatic that are very responsive to CD16 stimulation and less re- NK cell memory, however, the formation of these MCMV- sponsive to other cytokine or activating signals, recapitulating reactive NK memory cells required what is now a well-defined the observed Ag specificity of a memory cell (42). Indeed, the 2 interaction between the NK cell activating receptor, Ly49H, g phenotype might be more important to CMV-reactive and the m157 protein of MCMV (37). Although the NK cell memory NK cells than NKG2C, because an expanded NK memory response to MCMV infection in mice mirrors the Ag cell memory population exists in HCMV+ humans that lack dependence of hepatic memory, it is characteristically distinct NKG2C expression. In both NKG2C-null individuals, as well from hepatic memory, in that the recall responses generated as in those with NKG2C, effective CMV-reactive memory is through Ly49H are restricted to m157 Ag recognition unlike correlated with CD2 activity synergizing with CD16 to pro- the adaptable capacity hepatic memory NK cells exhibit to a vide protection (43). variety of Ags. Later experiments showed that NK cells If the hallmark of adaptive hepatic memory is its Ag expressing Ly49D, the other B6 mouse activating receptor, specificity, the hallmark of CMV-reactive memory is this could also undergo expansion, contraction, and memory pool notable expansion and contraction that the relevant NK cell formation upon exposure to their target Ag, the H-2d MHC-I pool undergoes, whether it expresses Ly49H (4), NKG2C molecules, provided that a virus infection was ongoing at the (35), or CD16 (44) as its activating receptor. Further research time (38). has uncovered key features of these phases. Expansion requires The MCMV-mediated NK cell memory phenomenon the transcription factor Zbtb32 (45) and is at least somewhat might have been dismissed as a mouse-specific oddity, part of dependent on the cytokines IL-12 (46), IL-18 (47), and IL-33 the ongoing and well-documented arms race between CMV (48), all of which are induced following CMV infection, as and NK cells, except that a similar pattern was noticed in well as the intracellular isoform of osteopontin (49). IFNAR humans. Around 40–70% of the population is infected with is also required for an efficient memory expansion: although ‒ ‒ human CMV (HCMV) (39). HCMV+ individuals, like the IFNAR / NK cells expand normally upon CMV challenge, MCMV-infected mice, tend to have a noticeably expanded they are quickly killed off and do not lead to a memory pool population of NK cells; in this case, these cells are marked by (50). Contraction is also a regulated process that is necessary their NKG2C expression (35). Further study of these cells for an effective NK cell memory response. Mice lacking the has revealed a signature surface phenotype: they tend to be proapoptotic factor Bim have too little contraction, resulting The Journal of Immunology 2871 in an uncharacteristically large but ultimately nonprotective cytokine memory state begins to fade by 21 d and, under some Ly49H+ pool of NK cells following MCMV challenge stimuli, cannot be detected after 4 wk (57, 61). Compare this (51). Conversely, mice lacking mitophagy display too much to reports of adaptive NK cell memory present after 4 mo in memory contraction and similarly fail to develop protective mice (8), a year in macaques (10), or 9 mo (41) to several memory (52). decades (11) in humans. Cytokine-induced memory-like re- Ultimately, the successful formation of a CMV-reactive sponses are also similar to a recently observed phenomenon memory pool is correlated with protection from a number among innate monocytes called cellular training, whereby a of diseases. Leukemia outcomes are better following a bone monocyte activated through any stimulus displays an enhanced marrow transplant if there is a CMV-reactive memory NK cell responsiveness to any future stimulus (65). In monocytes, this expansion (53), and HIV-exposed seronegative individuals is attributed to histone marks allowing faster transcription of have expanded CMV-reactive memory NK cells with very inflammatory genes (32, 66), similar to the demethylation high IFN-g expression (54). Moreover, the CMV-reactive patterns observed in memory versus naive NK cells. It may be memory NK cells are resistant to myeloid-derived suppres- that the cytokine-induced memory-like state is another example sor cell–imposed inhibition (55), making them promising of cellular training. agents in attempts at cancer immune therapies. Cytokine-induced memory-like NK cells. Around the same time Reuniting NK cell memory that CMV-reactive cells were discovered, work from the Even in this brief overview, it is clear that the three types of NK Yokoyama group reported yet another memory phenotype cell memory are phenotypically distinct (Table I). Adaptive Downloaded from in NK cells. They found that NK cells previously activated hepatic memory is characterized by its Ag specificity, whereas with IL-12 and IL-18 were much more responsive to IL-15 cytokine-induced memory-like NK cells are noticeably non- than naive cells in terms of proliferation and IFN-g specific, and CMV-reactive NK cells are Ag dependent, but expression (5). This was later recapitulated in vivo (56) and are only as specific as the battery of activating receptors they expanded to include many different stimuli, including cross- express: that is, Ly49H+ cells will react to m157, Ly49D+ cells linking Ly49H or NKR-P1C (5), coculturing with the YAC-1 will react to H-2d, and double-positive cells will readily react http://www.jimmunol.org/ cancer cell line (57), or LPS-induced inflammation (58), all of to both (38). However, there are also some marked similari- which could provoke a stronger response from preactivated ties between the three types, enough that considering the three cells than from naive. This lack of Ag specificity gave rise to as facets of the same response can be a useful exercise in the term “memory-like,” because the classical definition of broadening our understanding of NK cell memory. immunological memory includes both enhanced recall responses Although the distinctions in Ag specificity of memory re- and Ag specificity, but these cells were clearly carrying memories sponses mediated by hepatic memory NK cells and MCMV- of a previous activation state. The enhanced responsiveness of reactive NK memory cells could reflect intrinsic differences in cytokine-activated cells persisted for 3–4 wk in most reports and expression, binding, and signaling characteristics of the NK cell by guest on September 29, 2021 was stable after two or three generations of NK cell division receptors involved, the resultant memory formation mediated in an adoptive transfer model, so could not be explained as by each receptor shares a common cytokine requirement. simply residual activation from the cytokine stimulation (5, Adaptive hepatic memory fails in mice lacking IL-12 (28), and 56). Keeping with this generational stability, one study there is mounting evidence that the inflammasome, respon- found that the cytokine-induced memory-like NK cells had sible for the release of active IL-18, is central to inducing NK distinct demethylation across immune promoters; this pattern cell memory responses (30, 31). Similarly, mice lacking either was more similar to a CD8 T cell’s promoter landscape than the IL-12 (46) or IL-18R (47) fail to form a CMV-reactive that of a naive NK cell (59). memory pool on MCMV challenge, although IL-18 was not In contrast to adaptive hepatic memory, cytokine memory’s required for other, non-CMV–induced NK cell expansion. hallmark is a noted lack of Ag specificity. It appears to result Additionally, the osteopontin requirement for these cells ap- from several combinations of cytokine pretreatment, with pears to be mediated through the IL-15 cytokine (49). Finally, both IL-12 + IL-15 and IL-12 + IL-18 resulting in enhanced IL-12 and IL-18, alongside a survival cytokine like IL-2 or IL- responsiveness to various stimuli (5, 56, 60, 61). It also can 15, are the core cytokines needed to generate cytokine- arise from vaccination directly, as NK cells from influenza- induced memory-like NK cells (5). In this way, a common vaccinated individuals were more responsive to IL-12 + IL-15 cytokine milieu appears to be critical in determining whether or IL-12 + IL-18 (60). Similarly, a rabies vaccine was reported Ag encountered by NK cells leads to a protective memory to enhance NK cell IFN-g in an IL-12 + IL-18–dependent population. manner, although this also required IL-2 from CD4 T cells The accumulated evidence from the study of NK cell (62). Along these lines, human cytokine-induced memory-like memory suggests that these responses are only differentiated on cells were observed to increase their expression of CD25 and their method of generating Ag specificity, one of which is still were much more IL-2 sensitive than naive NK cells (63). The unknown. Different phenotypes of NK cell memory are based observed roles for cytokine-mediated formation of memory in only on the different receptors used to generate Ag specificity. NK cells is akin to the essential memory cell programming This may also dictate the extent of Ag specificity or “Ag roles that cytokines IL-12 and IFN-a/b play in determining adaptability,” such as to either a broad array of Ags, as seen whether naive CD8 T cells form a protective memory pop- with Ly49C/I (Fig. 2), or a limited Ag type, as by Ly49H. ulation following Ag exposure (64). The cytokine requirements shared across the different forms Beyond a lack of specificity, cytokine-induced memory-like of NK cell memory can be understood as priming signals for responses are fairly short-lived. Although it is stable across NK cells, which only support the formation of a long-lived several generations of NK cells in adoptive transfers, the NK cell memory pool that acquires Ag specificity. This 2872 BRIEF REVIEWS: Ly49 RECEPTORS IN NK CELL MEMORY

Table I. Key characteristics of NK cell memory responses types

Adaptive Hepatic CMV-Reactive Cytokine-Induced Memory Response Memory Response Memory-like Response Cells involved Liver-homing NK cell or ILC1 Conventional NK cells Conventional NK cells (possibly liver-homing NK cells or ILC1) Ag specificity Ag specific and Ag adaptable Ag dependent Nonspecific (trained immunity) Cytokine requirement IL-12, IL-18 IL-12, IL-18, IL-33 IL-12 1 IL-15, IL-12 1 IL-18 Ag tested Haptens, peptides, whole protein, MCMV (m157), HCMV LPS, influenza and rabies vaccine viruses (Ebola, HIV1, HSV-2, influenza A/B, vesicular stomatitis virus), S. Typhimurium, tumors Key receptors involved Ly49C/I, CXCR6, IL7Ra, CD49a Ly49H, CD16, NKG2C (human) N/A References (3, 8, 9, 12–17, 21, 28, 29) (4, 35, 37, 40, 44, 46–48) (5, 56–61) N/A, not applicable. parallels the very same cytokine requirements observed for Ag- also expressed Ly49D (38), NKG2C+ memory NK cell ex- specific T cells to undergo memory formation. Viewed in this pansion correlates with improved leukemia survival (53), and light, it is possible to understand a single type of NK cell an HIV-exposed seronegative status correlates with potent memory, which relies on the “prememory” or “trainable” state CMV-reactive memory (54). Downloaded from from cytokine induction that is guided by the Ag-sp. act. of One potential solution to this disparity in responses is the 2 one or more NK cell receptors. correlation of the g CD16-dependent NK cell memory cells Additionally, evidence is emerging that suggests there may with CMV memory status. Of note, the study that found be more similarities between the Ag specificity displayed by reduced cross-reactivity of Ly49H+ memory cells to influenza adaptive hepatic NK cells and CMV-reactive NK cells than virus or Listeria did so in a very controlled, adoptive transfer originally appreciated. In humans, alterations in HLA-E model, where no Ab response to either influenza virus or http://www.jimmunol.org/ peptide presentation from HCMV infection has been asso- Listeria could have occurred. Conversely, the studies that ciated with changes in the resulting NK cell memory response found broadly enhanced protection from the CMV-reactive (67, 68). Exploring the relevance of this finding in the context memory cells did so by observing complex immune situations, of CMV-reactive NK cell memory goes beyond the scope of which likely had some involvement from Ab responses. + + this review; an article doing just that has recently been pub- Much like how Ly49H Ly49D NK cells could efficiently act lished by Ro¨lle and colleagues (69). For our purposes, it is through both receptors, CMV-reactive cells that also express enough to note that in both adaptive hepatic and CMV- CD16 would be broadly active against any target for which reactive forms of NK cell memory, we now have evidence there was an Ab response because a variety of Abs all signal by guest on September 29, 2021 that a C-type lectin complex (Ly49 and NKG2C/CD94, re- through CD16. In support of this, CMV-reactive memory cells spectively) expressed by the memory NK cell has a direct were reported to be effective against influenza virus infection, involvement in recognizing MHC-I–presented peptide changes but only in the presence of influenza virus-reactive Abs (44). and driving the resulting memory response. Again, this is not Put another way, all forms of NK cell memory are only able to say that these two lectin:MHC interactions are identical; in to react to stimuli for which they have a receptor. In the case of CMV-reactive memory, these cells tend to coexpress CD16 particular, NKG2C is an activating receptor, whereas the and so will be broadly active memory cells, recognizing any- Ly49 receptors that drive adaptive hepatic NK cell memory thing that an Ab can recognize. In the case of adaptive hepatic are inhibitory. Instead, we take this as further support that NK cells, these cells are reported to be less likely to express the different NK cell memory phenotypes are more akin to CD16, explaining their more rigid Ag recognition. Granted, variations on a common theme than to truly distinct cellular this tendency for CMV-reactive memory cells to coexpress phenomena. CD16 and for adaptive hepatic memory cells to avoid it may Given the broad array of activating and inhibitory receptors indicate that these are two fundamentally distinct forms of NK NK cells possess, having several strategies for acquiring Ag cell memory. Instead, however, there may be a single NK cell specificity is not surprising and may not indicate fundamen- memory precursor, which stochastically either expresses CD16 tally different responses if a different method of specificity is or not and which will then develop into either a broadly- used. One question this model does not address is the vari- reactive CD16+ NK cell memory cell or a narrowly focused 2 ability in how specific an NK cell memory response is. CD16 cell (Fig. 4). Hopefully, a deeper understanding of Adaptive hepatic responses are very specific, only responding to how hepatic memory cell specificity is generated will answer challenge Ags that match the sensitization Ag. Conversely, this question. there are mixed reports with CMV-reactive memory. In some cases, it too is reported as very specific: mice with robust CMV- Clinical significance of NK cell memory reactive memory pools were observed to have blunted re- The study of NK cell memory is still in its infancy, and so there sponses to influenza virus or Listeria (70), and a recent report are few examples of its applicability in clinical medicine. Al- indicates that CMV-reactive NK cells undergo avidity selec- ready, however, a clinical trial in a small cohort of acute tion during expansion, which could further increase their myeloid leukemia patients has indicated that transplantation specificity (71). However, in other cases, there appears to be with cytokine-induced memory-like NK cells shows clinical no conflict in cross-reactivity. As mentioned above, Ly49H+ promise; donor memory NK cells were associated with an memory NK cells could respond well to H-2d provided they improved antileukemia response ex vivo and ultimately an The Journal of Immunology 2873

FIGURE 4. A unified model of NK cell memory, in which the cytokine-induced memory-like state induced in cells with heterogeneous activating receptor Downloaded from expression can lead to diverse NK cell memory phenotypes from the same underlying process. The cells that mediate adaptive hepatic memory may originate from liver-homing type I innate lymphoid cells or NK cells. overall response rate of 55% (72). Similar results in a prememory NK cells coexpressing Ly49H and Ly49D or clinical xenograft model of ovarian cancer suggests that this CD16, memory NK cells can express a battery of activating benefit may be extensible into solid tumors as well (73). receptors and respond to targets that are recognized by any http://www.jimmunol.org/ Additionally, as mentioned above, preliminary studies have of these receptors, making it likely that a memory CAR-NK shown that bone marrow transplants from donors with a pool cell can better control escape mutants than a CAR-T cell, of CMV-reactive memory NK cells result in improved anti- becausethemutantwouldhavetoescaperecognitionfrom leukemia outcomes (53). Together, these findings suggest that the CAR itself as well as any Ab signaling through CD16 NK cell memory could be clinically relevant for improving and any normal NK cell stress sensing through the natural cancer outcomes even without specific Ag targeting. Indeed, cytotoxicity receptors. advances in oncolytic virus therapy have focused on engi- neering viruses that infect tumor cells and simultaneously Conclusions by guest on September 29, 2021 deliver immune-modulating cytokines and chemokines (74– In reviewing the three types of NK cell memory, we have 76). An oncolytic virus that delivers IL-12 and IL-18 after highlighted their similarities and differences, and in so doing infecting a cancer cell could establish the ideal environment have proposed that these three types of memory may in fact be for naturally developing adaptive NK cell memory to the facets of the same response. Cytokine induction primes the NK cancer in question without having to uncover and design cell to become a memory cell, and then Ag specificity, either relevant peptide targets against that cancer. through the Ly49C/I-related mechanism of hepatic memory or If we understand NK cell memory as a single response that through a germline receptor like NKG2C, Ly49H, or CD16, arises from the combination of the correct cytokine milieu commits the cell to an Ag-specific memory cell. Unfortunately, (IL-12 + IL-15 + IL-18) and the stochastic expression of the an incomplete understanding of this immune phenomenon relevant receptor (Ly49H, CD16, Ly49C/I, etc.), it is possible prevents a definitive analysis of whether NK cell memory is one that introducing new relevant receptors to NK cells could or several distinct processes. However, it is our hope that by expand the possibilities offered by NK cell memory. Already, focusing on the similarities between these forms of memory, NK cells are being examined as targets for chimeric Ag receptor the three fields can each be strengthened by each other’s (CAR) therapy for a number of reasons, including their po- findings, and together we can advance our understanding of a tential for reduced toxicity and dramatically reduced cost novel immune response that has already shown potential in when compared with more traditional CAR T cell–based cancer vaccines, HIV therapy, tuberculosis, and many other approaches (77, 78). Currently, CAR-NK cells are generated health care challenges. by expanding NK cells from cord blood or the NK-like NK- 92 cell line using IL-2 or IL-15. However, if our unified Acknowledgments model of NK cell memory is correct, it would predict that We thank members of the Makrigiannis laboratory for critical reading of the CAR-NK cells expanded in the presence of IL-12 and IL-18 manuscript. would exist as memory NK cells when introduced into the patient. This is especially enticing, because memory NK cells could exhibit enhanced activity against their target on a cell- Disclosures The authors have no financial conflicts of interest. by-cell basis, independent of any enhanced activity from the clonal expansion of the memory NK cell (4, 28), meaning that these memory CAR-NK cells would be more effective References 1. Ka¨rre, K., H.-G. Ljunggren, G. Piontek, and R. Kiessling. 1986. Selective rejection cancer controllers than might be predicted based on the of H-2-deficient lymphoma variants suggests alternative immune defence strategy. study of naive NK cells. Additionally, as observed with Nature 319: 675–678. 2874 BRIEF REVIEWS: Ly49 RECEPTORS IN NK CELL MEMORY

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