IL‐15 Induces Alloreactive CD28 − Memory CD8 T Cell Proliferation and CTLA4‐Ig Resistant Memory CD8 T Cell Activation

The presence of CD28 − memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA‐4Ig induction therapy. In vitro analyses have indicated poor alloantigen‐induced CD28 − memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28 − memory CD8 T cell proliferation. Addition of IL‐15, but not IL‐2 or IL‐7, to co‐cultures of CD28 − or CD28 + memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28 − and enhanced CD28 + memory T cell proliferation. Proliferating CD28 − memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28 + memory CD8 T cells. CTLA‐4Ig inhibited alloantigen‐induced proliferation of CD28 + memory CD8 T cell proliferation but had no effect on alloantigen plus IL‐15‐induced proliferation of either CD28 − or CD28 + memory CD8 T cells. These results indicate the ability of IL‐15, a cytokine produced by renal epithelial during inflammation, to provoke CD28 − memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA‐4Ig‐mediated costimulation blockade.