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The major immunological barrier to allograft survival is HLA incompatibility. Such alloantigenic differences between a donor and recipient provoke T and B lymphocyte responses, which will result in graft loss unless immunosuppressive drugs are administered. Natural Killer (NK) cells, another type of lymphocyte in the mononuclear cell compartment, have not typically been considered a threat to solid organ allograft survival. Historically, NK cells were thought of as components of innate immunity based on their intrinsic ability to spontaneously kill target cells independent of HLA antigen restriction. However, it is now clear that NK cells are quite sophisticated and use a highly specific and complex target cell recognition receptor system arbitrated via a multitude of inhibitory and activating receptors (1).

Killer cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells development and function. To date, 14 distinct KIR have been identified: eight are inhibitory types and six are activating. The number and type of KIR genes present varies substantially between individuals. Inhibitory KIR recognizes distinct motifs of polymorphic HLA class I (HLA-A, B or C) molecules. Upon engagement of their specific HLA class I ligands, inhibitory KIR dampen NK cell reactivity. In contrast, activating KIR are believed to stimulate NK cell reactivity when they sense their (unknown) ligands. KIR and HLA gene families map to different human chromosomes (19 and 6, respectively), and their independent segregation produces a wide diversity in the number and type of inherited KIR–HLA combinations, likely contributing to overall immune competency. Consistent with this hypothesis, certain combinations of KIR-HLA variants have been correlated with susceptibility or resistance to diseases as diverse as autoimmunity, viral infections and cancer (1).

Since NK cells circulate in a state that can spontaneously deliver lethal effector function, it is critical that they do not attack healthy cells. To prevent such a detrimental autoimmune response, NK cells express at least one inhibitory receptor to a self-HLA class I molecule. Interaction of inhibitory KIR with cognate HLA class I ligands further sets the threshold of NK cell functional competence. Abundant expression of HLA class I molecules on normal healthy cells provide ligands for a variety of inhibitory receptors of NK cells. As a consequence, healthy cells are tolerant to NK cell attack. Down regulation of HLA class I expression due to certain viral infections, neoplastic transformations or stress, releases their inhibitory influence on NK cells, permitting them to eliminate these unhealthy target cells. This phenomenon is known as the ‘missing-self’ hypothesis (2). Simply stated, unlike T and B cells, NK cells are activated by the absence of self-HLA class I molecules on the surface of target cells.

In allogeneic transplantation, recipient NK cells expressing an inhibitory receptor can be activated to mediate target cell killing when the allograft lacks the relevant HLA class I ligand for that inhibitory receptor (3). This can occur even within HLA compatible transplants (but not HLA-A, B, C identical transplants). In this issue of the American Journal of Transplantation, van Bergen et al. present results indicating that the absence of donor HLA class I ligands for recipient inhibitory KIR is associated with reduced long-term graft survival in HLA-A, B, DR compatible kidney transplants (4). In fact, among HLA-DR compatible kidney transplants, the impact of inhibitory KIR–HLA ligand mismatches on 10-year graft survival was comparable to the impact of classical HLA-A and HLA-B incompatibility. Multivariate Cox regression analysis confirmed the effect of KIR-ligand mismatching as an independent risk factor (4). The authors propose that NK cell alloreactivity due to missing HLA class I ligand for the recipient's KIR is what hampers renal allograft survival in this setting. While the data are associative and do not address causality, they are nonetheless provocative findings that would have direct clinical relevance since NK cells are not targeted effectively by current immunosuppressive therapy. But before changing therapeutic strategies, the precise mechanism(s) by which (or if) the missing ligand for recipient NK cells results in allograft loss must be elucidated. Questions that need to be addressed include: (1) does a missing ligand for recipient NK cells provoke direct cytolysis of the allograft or is it cytokine secretion that enhances a T cell alloresponse?; (2) is the missing ligand sufficient to provoke NK effector function or is there a requirement to combine with an activation signal (processed through NKG2D and/or any of the activating NK cell receptor) to mediate effector function?; (3) could the missing ligand for recipient NK cells be harnessed and contribute to tolerance induction by killing graft-derived antigen presenting cells?

The study analyzed the four well-recognized inhibitory KIR-HLA ligand pairs, namely KIR2DL1 + HLA-C2, KIR2DL2/L3 + HLA-C1, KIR3DL1+HLA-Bw4 and KIR3DL2 + HLA-A3/11. The strength of inhibitory signals triggered by these four receptor–ligand interactions can vary based on the sequence polymorphism of KIR receptor, HLA ligand, as well as HLA-loaded peptide. For instance, the inhibitory signals triggered by the KIR2DL2/3 + HLA-C1 interaction are relatively weaker than those triggered by the KIR2DL1 + HLA-C2 interaction (1). Due to the small sample size, this study did not identify which, if any, of these four receptor–ligand mismatching is more detrimental to the allograft than the others. Furthermore, the study did not establish whether donor: recipient pairs with multiple receptor–ligand mismatching were more likely to have enhanced NK cell alloreactivity and vigorous allograft damage compared to pairs with single receptor–ligand mismatch.

Using an in vitro system, a previous study revealed that renal allograft recipients carrying more activating KIR genes triggered greater NK cytotoxicity against their donors’ peripheral blood mononuclear cells than recipients carrying fewer activating KIR genes (5). However, van Bergen's study (4) did not find an association between allograft survival and any activating KIR genes or group-B KIR haplotypes featured with more activating KIR genes. It is important to note that activating KIR receptors and not inhibitory receptors have been most prominently implicated in clinical settings (1). Patients who were transplanted for acute myelogenous leukemia with donors having group-B KIR haplotypes (having more activating KIR) have improved relapse-free survival. A series of genetic epidemiological data have revealed the association of distinct activating KIR in antiviral immunity, autoimmune diseases and cancer progression.

In summary, the study by van Bergen et al. (4) represents the first evidence for missing donor HLA class I ligands for recipient inhibitory KIR influences NK cell response towards allograft rejection. While these data make it tempting to speculate that suppression of NK cell activity will improve long-term renal allograft survival, confirmatory evidence is clearly necessary. In fact, a multicenter study with a larger cohort of HLA compatible renal transplants was recently launched by van Bergen and Doxiadis as a component of the 16th International HLA and Immunogenetics Workshop (http://16ihiw.org/projects/bergen_nkrole.html). Such studies are needed to unravel the ramifications of specific and multiple inhibitory KIR–HLA ligand mismatches and validate that recipient KIR independently influence renal allograft survival. Despite their associative nature, the genetic findings by van Bergen et al. (4) provide an intriguing and testable hypothesis.

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The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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