Increasing the duration of cold ischemic storage (CIS) from 0.5 to 8 hrs prior to transplant induces the increased proliferation of endogenous donor-reactive CD4 and CD8 T cells in cardiac allografts within 24 hours of reperfusion and the effector functions of these activated memoryCD8 T cells directly mediate CTLA-4Ig-resistant rejection of the higher risk allografts. The increased proliferation of endogenous CD8 T cells within the higher risk allografts requires CD4 T cell help via CD40-CD154 interactions with graft dendritic cells to induce IL-12p40 production that is required for endogenous memory CD8 T cell proliferation and CTLA-4Ig resistant rejection. The goal of the current study was to identify the memory CD4 and CD8 T cells proliferating with allografts subjected to minimal vs. prolonged CIS. When the phenotype of the infiltrating CD4 and CD8 T cells was more closely examined, naïve (CD62L^lowCD44^low) and effector memory (CD62L^lowCD44^high) and central memory (CD62L^highCD44^high) phenotype CD4 and CD8 T cells were identified within the allografts subjected to either minimal or increased CIS. Only effector memory CD4 and CD8 T cells proliferated within allografts subjected to 0.5 hr CIS. In contrast, both central and effector memory CD4 and CD8 T cells proliferated within allografts subjected to 8 hrs CIS, but only a small proportion (5-10%) of the proliferating CD8 T cells expressed IL12Rβ1 and β2. This suggested that p40 homodimers may provoke memory CD8 T cell proliferation within the higher risk allografts indirectly rather than by directly binding to IL-12Rb1 on the endogenous memory CD8 T cells. Therefore, we investigated other candidate factors to drive this memory CD8 T cell proliferation. qPCR analysis of memory CD8 T cells isolated from allografts showed increased mRNA expression of IL2Rα (CD25),β (CD122) and IL15Ra in infiltrating CD8 T cells purified from allografts subjected to prolonged vs. minimal CIS on day 2 post-transplant. Peri-transplant treatment with anti-CD122 or anti-CD127 mAb decreased the proliferation of endogenous memory CD8 T cells within highly ischemic allografts and abrogated CTLA-4 Ig resistant rejection mediated by the endogenous memory CD8 T cells. These results suggest that p40 homodimers stimulate the production of proliferative cytokines, possibly IL-15, which binds IL2Rβ on CD8 T cell followed by their proliferation within allografts subjected to 8 hr CIS.

CITATION INFORMATION: Tsuda H., Valujskikh A., Fairchild R. p40 Homodimer Induced Proliferation of Endogenous Donor-Reactive Memory CD8 T Cells within High Risk Allografts Requires Memory CD8 T Cell Expression of CD122 Am J Transplant. 2017;17 (suppl 3).

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