*Purpose: Acute allograft injury occurring during the first 1-2 days post-transplant is mediated by graft infiltrating endogenous donor-reactive memory CD8 T cells and requires their proliferation within the graft. We reported that longer graft cold ischemic storage (CIS) times before transplant increases endogenous donor-reactive mCD8 T cell proliferation within complete MHC-mismatched murine cardiac allografts 1-2 days post-transplant and their expression of effector functions that mediate CTLA-4Ig-resistant graft rejection. The increased mCD8 T cell proliferation within such high-risk allografts requires p40 homodimers (p40HD) produced by graft DC.

*Methods: Here we investigated mechanisms underlying p40HD-induced endogenous mCD8 T cell proliferation within the heart allografts.

*Results: Purified CD8 T cells infiltrating allografts subjected to 8hr CIS expressed increased CD25 and CD122 mRNA levels on day 2 post-transplant with marked increases of IL-15, but not IL-2, protein in the graft. Blocking IL-15 signaling with anti-CD122 mAb inhibited early endogenous mCD8 T cell proliferation within high-risk allografts and prolonged graft survival in CTLA-4Ig conditioned recipients from day 18.5 with rat IgG treatment to day 53 median survival time (MST). Consistent with this, p40HD injection into recipients of low-risk allografts increased graft IL-15 mRNA and protein and the increased mCD8 T cell proliferation in the grafts was inhibited by anti-CD122, but not anti-CD25, mAb. To identify the allograft cells producing p40HD-induced IL-15, we transplanted hearts from diphtheria toxin (DT) receptor-CD11c transgenic mice. DT-mediated depletion of graft 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. Use of IL15Rα-/- mice as donors of high ischemic allografts decreased early endogenous mCD8 T cell proliferation within grafts and extended graft survival in CTLA-4Ig conditioned recipients vs. wild-type allografts from day 33 to 69 MST.

*Conclusions: These results indicate that p40HD stimulate graft DCs to produce IL-15 that directly drives endogenous donor-reactive mCD8 T cell proliferation in high ischemic heart allografts to mediate CTLA-4Ig resistant rejection. This regulation of donor-reactive mCD8 T cell activation within allografts identifies novel targets to attenuate CTLA-4Ig resistant rejection mediated by these mT cells.

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