The Natural Killer Cell Receptor NKG2D is Critical to Antibody-Mediated Chronic Rejection in Heart Transplantation

Abstract

Natural killer (NK) cells are key components of the innate immune system. Prior animal studies have shown that donor-specific antibodies (DSA) in concert with NK cells are sufficient to inflict chronic allograft vasculopathy (CAV), but only with certain donor/recipient combinations. Current understanding of NK cell biology suggests the transition from quiescence to activation is mediated by a network of activating and inhibitory receptors; it is the integration of these signals that determines the final response. We hypothesized that the varying susceptibilities observed to this NK cell-mediated injury were due to differences in either donor activating ligand expression or recipient NK cell phenotype(s). We utilized a murine model of cardiac transplantation with C3H (H-2k) or BALB/c (H-2d) hearts engrafted into immune-deficient C57Bl/6 Rag1-/- (H-2b) recipients. Recipients had no functional T or B cells, but an intact innate immune system. Experimental recipients received monoclonal Class I antibodies (anti-H2k for C3H donors, or anti-H2d for BALB/c donors). Allografts and recipient NK cells were recovered and examined after 30 days. Allografts from C3H donors demonstrated marked neointimal changes consistent with CAV. Conversely, allografts from BALB/c donors were protected despite this donor / recipient combination also representing a fully allogeneic mismatch (Figure 1A). There was no difference in recipient NK cell phenotype or ability to be activated between the two groups. Analysis of allograft endothelial cells from C3H allografts, however, showed significantly higher expression of the activating NKG2D ligand Rae-1 (Figure 1B). Significantly, administration of an NKG2D blocking antibody abrogated the development of vasculopathy in recipients of C3H allografts, even in the presence of DSA (Figure 1A). NKG2D ligand / receptor engagement is necessary in this antibody-dependent form of chronic cardiac allograft vasculopathy.