Direct comparison of transplant- vs. infection-induced CD8+ T cells role of mTOR signaling, including during CD154:CD11b blockade 4036

Abstract Description Solid organ transplant recipients require lifelong immunosuppression that attenuates graft rejection but increases susceptibility to infection and cancer. Studies have identified immunosuppressive targets that effectively prevent graft rejection but paradoxically improve response to infection, including mTOR and Coronin-1. Using murine models of Epstein Barr virus (MHV68) infection and skin transplantation, we found that CD154:CD11b pathway blockade significantly decreased the graft-elicited CD8+ T cell response but increased the quantity and quality of the virus-elicited CD8+ T cell response. Direct comparison of OVA-specific TCR transgenic OT-I T cell responses to MHV68-OVA infection vs. mOVA skin grafts allowed us to interrogate what pathways may be altered to lead to these dichotomous outcomes. OT-I T cells elicited via skin grafts significantly increased the expression of phospho-S6, a ribosomal protein downstream of mTOR signaling, on day 10 compared to OT-I T cells elicited via an infection. Transplantation also induced altered expression of T-bet, Eomes, and TCF-1, which are known to be altered by mTOR signaling, and a significant decrease in PD-1+Tim-3+TCF-1- terminally differentiated cells. In sum, graft- vs. infection-elicited CD8+ T cell responses are underpinned by altered mTOR signaling. Determining the effect of potential immunotherapeutics on mTOR could identify targets that inhibit the alloreactive CD8+ T cell response without impairing protective immunity. Funding Sources Supported by NIH R01AI152516 Topic Categories Transplantation Immunology (TRAN)