Neither NK cells nor host innate immune signaling through the common cytokine receptor gamma chain are required for islet xenograft rejection
Background While CD4+ T cells alone show limited ability to reject islet allografts, CD4+ T cells are both necessary and sufficient to trigger vigorous islet xenograft rejection. NK cells have often been implicated as an innate host immune component that may contribute to the potency of cellular xenograft rejection. To determine whether NK cells contribute to CD4 T cell-mediated xenograft rejection, we utilized immune deficient (RAG−/−) mice also lacking the common cytokine receptor gamma chain (γc) required for NK development. By reconstituting these immune deficient animals with CD4+ T cells, we determined whether NK cells contributed to CD4 T cell-mediated xenograft rejection.
Materials and methods 450 WF islets were transplanted beneath the renal capsule in streptozotocin-induced diabetic RAG−/− or NK-deficient RAG−/−γc−/− mice. Parallel phenotypic and functional studies confirmed the absence of detectable NK activity in RAG−/−γc−/− mice, consistent with previously published reports. Transplanted mice were subsequently reconstituted with 5 × 106 purified CD4+ T cells. Donor CD4+ T cells were depleted of NK1.1+ cells in some cases.
Results Unreconstituted RAG−/− or RAG−/−γc−/− mice uniformly accepted rat islet xenografts >60 days. Reconstitution with CD4+ T cells triggered acute rejection of WF islet xenografts in either NK-replete RAG−/− (5/5 grafts rejecting in 19.6 ± 1.7 days) or in NK-deficient RAG−/−γc−/− (5/5 grafts rejecting in 11.2 ± 0.2 days recipients. Depletion of NK1.1+ cells from the donor CD4+ T cells prior to adoptive transfer resulted in equally vigorous xenograft rejection, indicating the NK cells from the donor T cell innoculum were not responsible for vigorous xenograft rejection. Furthermore, depletion of host NK1.1+ cells via monoclonal antibody therapy (HB191) in control RAG−/− mice did not impede xenograft rejection triggered by the transfer of CD4+ T cells.
Conclusion These results indicate that NK cells are not required to amplify rapid rejection of islet xenografts triggered by CD4+ T cells. Importantly, since IL-2, 4, 7, 9, 15 all signal through the γc receptor, we also conclude that the innate immune system of the graft recipient need not recognize any of these cytokines for rapid cellular rejection of islet xenografts.