Memory T cells are critical components to protective immunity against recurrent pathogens, but memory T cells with donor-reactivity pose a major barrier to successful transplantation and tolerance induction. We have previously shown that endogenous donor-reactive CD8 memory T cells infiltrate murine cardiac allografts within hours of reperfusion, amplify early post-transplant inflammation by producing IFN-γ and perforin/granzyme B and directly mediate CTLA-4Ig resistant rejection of allografts subjected to prolonged cold ischemic storage. Here, we have sought to define the inflammatory signals and mechanisms driving their early increased number and activation within allografts subjected to prolonged ischemia. Using BrdU pulsing of graft recipients, memory CD4 and CD8 T cells infiltrating cardiac allografts subjected to prolonged vs. minimal (8 hours vs. 30 min) cold ischemic storage were stimulated to increased proliferation that peaked 48 hours after graft reperfusion and then began to subside. Recipient treatment with anti-CD40L mAb, unlike CTLA4-Ig, at the time of reperfusion significantly inhibited the early proliferation of graft infiltrating memory CD4 and CD8 T cells and greatly extended survival of cardiac allografts subjected to prolonged cold ischemic storage. Consistent with this, proliferation of the endogenous memory CD8 T cells within highly ischemic allografts was reduced to the low levels observed in allografts subjected to minimal cold ischemic storage when recipients were depleted of CD4 T cells or when allografts were depleted of dendritic cells or were deficient in expression of class II MHC or CD40. In the absence of recipient memory CD4 T cells, expression of IL-15 and IL-18 mRNA was reduced in highly ischemic allografts to the levels observed in allografts subjected to 30 min cold ischemic storage, but were restored by treating CD4 T cell depleted recipients with an agonist anti-CD40 mAb. Overall these results indicate that clonal expansion of endogenous memory CD8 T cells within high ischemic cardiac allografts requires the activation of graft infiltrating memory CD4 T cells and graft resident dendritic cells through CD40-40L interactions, similar to the immune response that occurs during de novo priming of naïve donor-reactive T cells within the secondary lymphoid organ draining the graft.

CITATION INFORMATION: Tsuda H, Tanaka T, Su C, Valujskikh A, Fairchild R. CD4 T Cell Mediated Help Is Required for Intra-Allograft Proliferation of Endogenous Memory CD8 T Cells and Their Ability to Mediate Rejection of Cardiac Allografts Subjected to Prolonged Ischemia. Am J Transplant. 2016;16 (suppl 3).

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