BACKGROUND. Although permanent engraftment is often achieved with new therapeutics, chronic rejection and graft failure still occur. As the importance of CD8 T cells in rejection processes has been underlined in various transplant models, and as interleukin (IL)-15 is involved in the activation of CD8 T cells, we hypothesize that CD8 T cell "escape" from costimulation blockade might be a IL-15/IL-15R dependent process. METHODS. In a murine islet allograft model employing a fully major histocompatibility complex-mismatched strain combination of Balb/c donors to CD4 C57BL/6 recipients, a monotherapy with the IL-15 antagonist, IL-15 mutant/Fcγ2a, or the costimulatory blockade molecule, CTLA4/Fc, was used. In addition to monitoring graft survival, infiltration of alloreactive immune cells was analyzed by histology and immunohistochemistry, and alloimmune response of proliferative CD8 T cells was measured in vivo. RESULTS. Sixty percent of the recipients treated with CTLA4/Fc acutely rejected their islet allograft, comparable to untreated control animals (50% survival). In contrast, the IL-15 antagonist proved to be highly effective, with 100% of recipients accepting their allograft. Immunohistology study demonstrated a remarkable decrease of CD8 T-cell intragraft infiltration in IL-15 mutant/Fcγ2a treated animals with well-preserved islet architecture and a reduced frequency of proliferating alloreactive CD8 T cells in comparison with that of untreated and CTLA4/Fc treated groups. CONCLUSIONS. In this study, we determined the efficacy and potential therapeutic benefit of the IL-15 antagonist on CD4-independent CD8 T-cell responses to alloantigens. Targeting the IL-15/IL-15R pathway represents a potent strategy to prevent rejection driven by CD8 T cells resistant to costimulation blockade.