Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells.

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade-induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4(+) and CD8(+) T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8(+) T cells directly mediate CTLA-4Ig-resistant allograft rejection. Memory CD8(+) T cell activation within allografts subjected to prolonged CIS requires memory CD4(+) T cell stimulation of graft DCs to produce p40 homodimers, but not 1L-12 p40/p3S heterodimers. Targeting p40 abrogates memory CD8(+) T cell proliferation within the allografts and their ability to mediate CTLA-4Ig-resistant allograft rejection. These findings indicate a critical role for memory CD4(+) T cell-graft DC interactions to increase the intensity of endogenous memory CD8(+) T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS.