title: Endogenous memory CD8 T cells directly mediate cardiac allograft rejection.
abstract: Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance-inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pretransplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen or adoptive transfer of donor antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here, we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming.
authors: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH; Glickman Urological and Kidney Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH.
authors: C A
authors: CA
authors: Su
authors: S
authors: S
authors: Iida
authors: T
authors: T
authors: Abe
authors: R L
authors: RL
authors: Fairchild
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D050377:Cold Ischemia; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007156:Immunologic Memory / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger
keywords: Cardiac allograft rejection; endogenous memory CD8 T cells; heterologous immunity; ischemia-reperfusion injury