Anti-CD154 limits murine Epstein-Barr viral burden and induces a decreased but more polyfunctional CD8+ T cell response 4032

Abstract Description Current FDA-approved costimulation blockade for use in organ transplantation significantly impairs the response to Epstein-Barr virus (EBV), increasing the risk of post-transplant lymphoproliferative disease (PTLD) and lymphoma. Anti-CD154 is a promising immunotherapeutic for solid organ transplantation with multiple ongoing clinical trials, but its impact on EBV immunity is unknown. In this study, we investigated the impact of anti-CD154 on the antigen-specific CD8+ T cell response to a YFP-expressing murine EBV homolog, MHV68. Results indicate that the frequency and number of virus-specific CD8+ T cells was significantly reduced following anti-CD154 treatment. However, CD8+ T cells in anti-CD154-treated mice also exhibited significantly lower frequencies of Tim-3+TCF1- terminally differentiated cells and an increase polyfunctional producers of IL-2, IFNγ, and TNFα compared to untreated mice. Of note, anti-CD154-treated mice had significantly smaller spleens with a significant decrease in the number of bulk and YFP+ germinal center B cells as compared to untreated mice on day 14. Overall, CD154 blockade significantly decreases the quantity but not the quality of EBV-specific CD8+ T cells. The ability of anti-CD154 to block the CD40 costimulation necessary for initiation of the germinal center response, limiting peak viral burden, may be a beneficial effect of anti-CD154 immunosuppression and may limit the potential for aberrant replication-associated complications like PTLD. Funding Sources Supported by NIH R01AI152516 Topic Categories Transplantation Immunology (TRAN)