NK cells promote peritoneal xenograft rejection through an IFN‐ γ ‐dependent mechanism

  Background:  Natural killer (NK) cells have emerged as major players in anti‐viral and anti‐tumour immune responses. Like cytotoxic T lymphocytes (CTL), they express perforin and are potent secretors of γ ‐interferon (IFN‐ γ ). However, there is conflicting evidence about their role in mediating rejection of xenogeneic tissue. Methods:  A pig‐to‐mouse peritoneal cell model of xenotransplantation was used to investigate the effect of NK deficiency on xenograft recovery and the possible mechanisms behind this NK‐mediated graft rejection. γ c −/− RAG −/− mice were used as a model of NK deficiency. Additionally, NK cells were depleted in RAG −/− mice using anti‐asialo GM1. The contributions of IFN‐ γ , perforin and NKT cells were studied using knock‐out mice that were depleted in vivo of T cells. Mice were injected with 10 7 pig cells intraperitoneally and peritoneal fluid was assessed 5 days later for xenograft recovery and phenotypic analysis. The requirement for NK cells for xenograft rejection was also assessed using luciferase‐transfected porcine cells in a renal subcapsular model of transplantation. Results:  Pig cell recovery was enhanced in both γ c −/− RAG −/− and NK‐depleted RAG −/− mice when compared with RAG −/− control mice. IFN‐ γ −/− mice depleted of T cells also demonstrated superior graft survival compared with their B6 counterparts. However, there were minimal graft survival differences between Pfp −/− and B6 control mice. Similarly, a deficiency in NKT cells did not improve pig xenograft recovery from the peritoneum of these mice. Conclusions:  Therefore, we conclude that NK cells, but not NKT cells, are important mediators of xenograft rejection in the peritoneal cavity, and that their role may be unmasked in the absence of T cells. The mechanism for this xenorejection appears to involve IFN‐ γ but is perforin independent.