Memory T cells with donor-reactivity pose a major barrier to successful allograft transplantation and tolerance induction. Longer cold ischemic storage (CIS) prior to transplantation promotes endogenous donor-reactive memory CD8 T cell infiltration into cardiac allografts and their activation thatdirectly mediates CTLA-4Ig-resistant rejection of the highly ischemic allografts between days 15-22 post-transplant vs. > 60 days for allografts subjected to the minimal CIS. Here, we have investigated mechanisms provokingthe increased endogenous memory CD8 T cell numbers and activation withinallografts subjected to 0.5 vs. 8 hrs CIS. Using BrdU labeling, graft-infiltrating memory CD4 and CD8 T cellssignificantly proliferated and accumulated within allografts subjected to 8 vs. 0.5 hr CIS. In contrast to the resistance following CTLA-4Ig treatment, peri-transplant recipient treatment with anti-CD40L mAb inhibited early graft infiltrating memory CD4 and CD8 T cell proliferation and markedly prolonged survival of allografts subjected to 8 hr CIS beyond day 40 post-transplant. The increased proliferation of endogenous memory CD8 T cells within the higher risk allografts required recipient CD4 T cells, graft dendritic cells and graft expression of class II MHC, CD40 and IL-12p40,but not p35.qPCR analysis showed that expression of IL-12p40but 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 the levels seen 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. Consistent with this, p40 homodimers, but not p70 heterodimers, were increased in allografts subjected to 8 hr CIS as well as in recipient serum and these increases were dependent on recipient CD4 T cells. Peri-transplant anti-p40 mAb reversed CTLA-4Ig-resistant rejection of higher risk allografts and peri-transplant p40 homodimers induced the proliferation of endogenous memory CD8 T cells within allografts subjected to 0.5 hr CIS to the levels observed in allografts subjected to 8 hr CIS. These data indicate that the activation of endogenous memory CD8 T cells within higher risk cardiac allografts requires CD4 T cell help via CD40-CD154 interactions with graft dendritic cells to induce their production of p40 homodimers.

CITATION INFORMATION: Tsuda H., Valujskikh A., Fairchild R. Graft Dendritic Cell p40 Homodimers Activate Donor-Reactive Endogenous Memory CD8 T Cells within Higher Risk Allografts Am J Transplant. 2017;17 (suppl 3).

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