Memory T cells provide protection against recurrent pathogens, but memory T cells with donor-reactivity pose a major barrier to successful allograft transplant and tolerance induction. We have previously shown that prolonged cold ischemic storage (CIS) promotes endogenous donor-reactive memory CD8 T cell infiltration into cardiac allografts within hours of reperfusion and these memoryCD8 T cells amplify early post-transplant inflammation and directly mediate CTLA-4Ig-resistant rejection of the highly ischemic allografts. Here, we have investigated mechanisms provoking the increased endogenous memory CD8 T cell numbers and activation within allografts subjected to 0.5 vs. 8 hrs CIS. Graft-infiltrating memory CD4 and CD8 T cells significantly proliferated and accumulated within allografts subjected to 8 vs. 0.5 hr CIS. Unlike CTLA-4Ig treatment, peri-transplant recipient treatment with anti-CD40L mAb significantly inhibited early graft infiltrating memory CD4 and CD8 T cell proliferation and markedly prolonged survival of allografts subjected to 8 hr CIS. The increased proliferation of endogenous memory CD8 T cells within highly ischemic allografts was reduced to the low levels observed in allografts subjected to 0.5 hr CIS when recipients were depleted of CD4 T cells or in allografts deficient in class II MHC, CD40, IL-12p40 or dendritic cells, but not in p35-deficient allografts. qPCR analysis revealed that expression of IL-12p40 but not IL-12 p35 or IL-23p19 mRNA was elevated at 48 hr post-transplant in allografts subjected to 8 hr vs. 0.5 hr CIS and the increase in p40 mRNA was reduced to that observed in 0.5 CIS allografts by depletion of recipient CD4 T cells, but was restored by treating CD4 T cell depleted recipients with agonist anti-CD40 mAb. Proliferating endogenous memory CD8 T cells expressed IL-12Rβ1 and Rβ2 within highly ischemic allografts. Treatment of recipients of 8 hr CIS allografts with anti-p40 mAb reversed CTLA-4Ig-resistant rejection and peri-transplant p40 homodimer treatment of recipients of 0.5 hr CIS allografts induced the proliferation of endogenous memory CD8 T cells to the levels observed in allografts subjected to 8 hr CIS. These data suggest that the activation of endogenous memory CD8 T cells within highly ischemic cardiac allografts requires CD4 T cell help via CD40-CD154 interactions with graft dendritic cells to induce p40 production.

CITATION INFORMATION: Tsuda H, Tanaka T, Su C, Valujskikh A, Fairchild R. Increased Ischemic Inflammation Induces Recipient Endogenous Memory CD4 Cell-Graft Dendritic Cell Interactions to Provide Help for Activation of Endogenous Memory CD8 T Cells. Am J Transplant. 2017;17 (suppl 3).

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