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Am J Transplant. 2014 Jun;14(6):1277-89. doi: 10.1111/ajt.12719. Epub 2014 May 19.

IL-15 induces alloreactive CD28(-) memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation.

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Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH; Division of Nephrology, Department of Internal Medicine, Thammasart University, Pathumthani, Thailand.


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.


Costimulation; T cell biology; belatacept; cytokines/cytokine receptors; immunosuppressant

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