Smad4 plays an integral role in memory CD8 T cell differentiation (IRM14P.444)

Abstract

Abstract Tissue resident memory CD8 T cells (TRM) are a unique subset of virus-specific CTLs which bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells (TCM) circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection however the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGFβ promotes the development of pulmonary TRM cells via a signaling pathway that does not require the downstream intermediate Smad4. In contrast, circulating memory CD8 T cells have no requirement for TGFβ but show signs of arrested development in the absence of Smad4 including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs, but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CTLs. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGFβ receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity.