IL-15 determines the role of Natural Killer cells in alloimmune response

Background: Transplant rejection is primarily mediated by adaptive immune cells such as T and B cells. However, the ongoing difficulty in creating transplant tolerance under T cell stringent conditions alone has stimulated renewed interests in the role of innate immune cells, especially NK cells, in transplant rejection and tolerance induction. Methods: We used Rag knockout mice as transplant recipients to critically examine the alloreactivity of NK cells in a stringent skin transplant model. The Rag mice lack T and B cells but possess a large fraction of functional NK cells, allowing us to study the role of NK cells in the absence of adaptive immune cells. Rag-IL-2Rγ double knockout mice which are also deficient for NK cells served as corresponding controls. Results: We found that Rag but not Rag-IL-2Rγ mice readily reject allogeneic DBA/2 cells. However, DBA/2 skin allografts were accepted by both Rag and Rag-IL-2Rγ mice indefinitely (> 100 days), demonstrating that NK cells by themselves, though cytolytic to DBA/2 cells, fail to reject the DBA/2 skin allografts. To test the hypothesis that the activation status of NK cells dictates their alloreactive potential, we treated the Rag mice with IL-15/IL-15Rα complex to maximally stimulate the NK cells. As expected, the IL-15 treated Rag, but not the Rag-IL-2Rγ controls, readily rejected the DBA/2 skin allografts (MST=18 days). Conclusions: Our data demonstrate that when fully activated and differentiated, NK cells are potent effector cells in allograft rejection. These findings may have important clinical implications in models of transplantation and autoimmunity.