Memory T cells generated in response to various viruses and environmental antigens are often cross-reactive to allogeneic MHC molecules. The presence of such endogenous donor-reactive memory (m) T cells prior to transplant is an established risk factor for increased acute rejection and poorer outcomes of clinical transplants. Another risk factor for poor clinical transplant outcomes is the time grafts are kept in cold ischemic storage (CIS) before transplant. We have reported that longer CIS times before transplant results in increased endogenous donor-reactive mCD8 T cell proliferation within complete MHC-mismatched murine cardiac allografts 24-48 hrs after transplant and in their enhanced expression of effector functions that mediate CTLA-4Ig-resistant allograft rejection. The increased mCD8 T cell proliferation within such high-risk allografts requires IL-12p40 homodimers (p40HD) produced by graft dendritic cells (DC) during interaction with allograft class II MHC-reactive mCD4 T cells. In this study we investigated mechanisms underlying p40HD stimulation of endogenous mCD8 T cell proliferation within the heart allografts early after transplant. Purified CD8 T cells infiltrating allografts subjected to longer CIS times expressed increased levels of mRNA encoding CD25, CD122 and IL15Rα on day 2 post-transplant and was accompanied by markedly increases in IL-15, but not IL-2, protein in the allograft. Blocking IL-15 signaling with anti-CD122 mAb inhibited endogenous mCD8 T cell proliferation within high-risk allografts at 48 hrs after transplant and prolonged allograft survival in CTLA-4Ig conditioned recipients to times observed in CTLA-4Ig conditioned recipients of low-risk allografts, from day 18.5 to 53 median survival time.  Consistent with this, p40HD injection into recipients of low-risk allografts induced increased graft IL-15 mRNA and protein and anti-CD122 mAb inhibited the p40HD-induced mCD8 T cell proliferation. To identify the allograft cells producing IL-15 in response to p40HD, we transplanted hearts from diphtheria toxin (DT) receptor–CD11c transgenic mice.  DT-mediated depletion of allograft CD11c+ cells prior to transplant abrogated p40HD-induced IL-15 production and endogenous mCD8 T cell proliferation within low-risk allografts, implicating graft DC as the IL-15 producers. This was confirmed using allografts from IL-15 reporter mice as graft donors.  Furthermore, use of IL15Rα-/- mice as high ischemic allograft donors decreased early endogenous mCD8 T cell proliferation within the allografts and extended survival in CTLA-4Ig conditioned recipients vs wild-type allografts from day 33 to 69. These results indicate p40HD induces graft DCs to produce IL-15 that directly stimulates endogenous mCD8 T cell proliferation within high ischemic heart  allografts to mediate CTLA-4Ig resistant rejection and identify novel targets to attenuate CTLA-4Ig resistant rejection mediated by these endogenous donor-reactive memory T cells.