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. IL-15 induces the activation of alloreactive CD28 - memory CD8 T cells and confers resistance of alloreactive CD28 + memory CD8 T cells to CTLA-4Ig-mediated inhibition. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.