Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-γ in response to donor class І MHC within 24 hrs after graft reperfusion in mice. Our recent studies have indicated that prolonged cold ischemic graft storage provokes intense inflammation within hours after allograft reperfusion and promotes endogenous memory CD8 T cell rejection of the allograft. Mechanisms underlying the accumulation of endogenous memory CD8 T cells in highly ischemic cardiac allografts were investigated. Complete MHC-mismatched hearts were subjected to minimal 0.5 hrs or 8 hrs of cold ischemic storage in University of Wisconsin solution and then transplanted to C57BL/6 (H-2b) mice. When assessed on day 2 post-transplant, proliferation of endogenous memory CD4 and CD8 T cells was increased 2-3-fold in highly ischemic vs. minimally ischemic cardiac allografts and this accounted for the increased numbers of these memory T cells in the allograft. Peri-transplant administration of CTLA-4Ig extended survival of minimal ischemic allografts from day 8 to day 50-60 post-transplant whereas survival of highly ischemic allografts was only extended from day 8 to day 15. In contrast, peri-transplant administration of anti-CD154 mAb extended survival of highly ischemic allografts to almost day 50. Depletion of CD4 T cells prior to the transplant of highly ischemic allografts decreased the proliferation and accumulation of endogenous memory CD8 T cells on day 2 post-transplant to the levels observed in minimally ischemic allografts. Similarly, peri-transplant administration of anti-CD154 mAb to recipients of highly ischemic cardiac allografts decreased the proliferation and accumulation of endogenous memory CD8 T cells within the allograft when assessed on day 2 post-transplant whereas administration of CTLA-4Ig did not affect endogenous memory CD8 T cell proliferation and numbers in the grafts. These studies suggest a role for CD4 T cells in providing helper signals to promote the proliferation of endogenous memory CD8 T cells within cardiac allografts subjected to prolonged cold ischemic storage and their function in directly mediating graft rejection.

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