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

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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 References This article cites 78 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/204/11/2867.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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).
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