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In View: Game Changer

An Unexpected Partnership

MHC Class II Molecules as Ligands for NK Cells

Wu, Chenglin MD, PhD1; Li, Xian C. MD, PhD2

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doi: 10.1097/TP.0000000000002973
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Natural killer (NK) cells are innate immune cells with potent cytolytic activities, and unlike components of the adaptive system including T cells and B cells, NK cells are ready to kill without prior antigen sensitization. Obviously, those potent cytolytic activities require tight control by multiple mechanisms that ensure NK tolerance to self while allowing cytolytic functions to proceed against “nonself” or “altered self” entities, including viral infected, stressed, and transformed cells.1 Thus, NK cells are a key in executing protective immunity and immune surveillance. In contrast to T cells and B cells, NK cells do not express the somatically rearranged clonotypic receptors allowing them to directly and specifically recognize foreign antigens. Instead, NK cells express a range of stimulatory and inhibitory receptors on their surface, balancing the variety of signals that collectively control their effector functions.2

Human NK cells constitutively express stimulatory and inhibitory killer cell immunoglobulin (Ig)-like receptors (KIR) on the cell surface that can bind to respective MHC class I molecules. Similar receptors in mice are called Ly49. Both KIR and Ly49 are critical in NK maturation, self-tolerance, and effector functions.3 During maturation, only those cells expressing the inhibitory KIR or Ly49 receptors that have productively engaged the self MHC class I molecules become killer cells, a process called NK “licensing” or NK “education.”4 In the periphery, mature NK cells constantly sense ubiquitously expressed self MHC class I molecules and achieve self-tolerance through the engagement of inhibitory KIR (or Ly49) receptors. Those “educated” NK cells readily become aggressive killers when self MHC class I molecules are mismatched, downregulated, or absent on target cells (ie, “missing self” recognition).5 Of note, some KIR and Ly49 receptors communicate activating signals in NK cells, and, when engaged beyond a threshold level, those NK cells may achieve cytolytic functions. Moreover, mature NK cells also express the NKG2 family of receptors (eg, NKG2D) that recognize ligands other than the MHC class I to facilitate NK activation, especially under inflammatory conditions.6

In both humans and mice, NK cells also express an additional set of activating receptors, so-called natural cytotoxicity receptors (NCR) consisting of 3 family members (NKp46, NKp44, and NKp30). NKp46 and NKp30 are constitutively expressed by all NK cells, whereas NKp44 is induced and expressed only on activated NK cells. In general, NCR have thus far shown to bind to stressed-induced proteins, tissue constituents, and pathogen derivatives but not, however, the MHC class I molecules.7

In the September issue of Nature Immunology,8 Niehrs and coworkers reported on a surprising and novel finding by showing that a subset of MHC class II molecules, specifically human HLA-DP molecules, may serve as ligands for the human NKp44 receptor capable of triggering NK effector functions. The authors asked whether NK cells had the capacity to specifically recognize HLA class II molecules. To this end, they made a series of IgG Fc fusion proteins, consisting of the ectodomain of multiple NK cell receptors (7 KIRs and 3 NCRs) and the Fc portion of the human IgG1. With that approach, they assessed the binding of such Fc fusion proteins to diverse HLA class II–coated beads (a total of 95 different HLA class II molecules tested). In a series of elegant experiments, the authors observed that only NKp44 among the 10 NK cell receptors tested had the capacity to bind HLA class II molecules. Interestingly, NKp44 only attached to HLA-DP with sufficient affinity but not to HLA-DQ and HLA-DR molecules. Moreover, they identified HLA-DP401 and HLA-DP201 but not HLA-DP601 and HLA-DP301 interacting with the NKp44. These data suggest a high degree of selectivity and specificity in the NCR-HLA class II interactions. The authors also confirmed their findings in an NKp44ξ-Jurkat reporter system, in which binding of HLA-DP401 to the NKp44 led to marked reporter activities (ie, CD69 expression), which was inhibited by blocking the NKp44 receptor. Such reporter activities were not observed with other HLA-DP allotypes. Importantly, when primary human NK cells had been activated with IL-2 and IL-15 to induce NKp44 expression, coculturing them in HLA-DP401 coated plates induced prominent CD107α expression, a marker of NK cytolytic activities. Notably, those effects could be inhibited by blocking NKp44. Those findings demonstrated for the first time that NK cells communicate directly with a subset of MHC class II molecules.

Why are those findings of relevance and significance in organ transplantation?

NK cells play a critical role in alloimmunity, tolerance, and chronic rejection, as well as during responses to injury, events in which NK cells often accumulate in substantial numbers in the grafts.9 The observation that the MHC class II molecules can directly interact with NK cells may thus help us develop new therapeutic approaches in the management of graft survival. Moreover, in contrast to MHC class I, MHC class II molecules are mainly expressed by professional APCs including dendritic cells which, in the transplant setting, include both donor and host-derived APCs. The NKp44-APC engagement may potentially amplify T cell priming for rejection (eg, interferon-γ production), trigger graft injury through direct NK cytolytic activities, or act as a switch in the mode of donor antigen presentation (eg, direct versus indirect pathway).10 Of note, NKp44 is only expressed by activated NK cells. In transplantation, infections and graft inflammation may trigger those events. Those scenarios also markedly upregulate the expression of MHC class II molecules on APCs. Thus, the NKp44-HLA class II interactions are highly relevant to organ transplantation and transplant-related complications.

Finally, the recent discovery that innate NK cells can acquire features of “adaptive immune cells,” including memory recall responses,11 clearly expands the role of NK cells in alloimmunity. The identification of NKp44 as a receptor for a subset of HLA class II molecules will undoubtedly be of relevance. Future studies are expected to detail the implications in protective immunity, autoimmunity, and transplantation.


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The observation that the MHC class II molecules can directly interact with NK cells may thus help us develop new therapeutic approaches in the management of graft survival.

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