Differential impact of TGF-ß signaling during distinct stages of mucosal CD8 resident memory T cell differentiation 4388

Abstract Description Resident memory CD8 T cell (TRM) development progresses through distinct stages comprising of initial activation of naive T cells into effectors in secondary lymphoid organs, trafficking of effectors to target tissue via blood, and final TRM differentiation at the tissue of residence under the influence of the local microenvironment. The cytokine TGF-β has emerged as a central regulator of epithelial TRM formation, but how TGF-β modulates these distinct stages of TRM differentiation is not known. Combining genetic mouse models that limit TGF-β availability or restrict CD8 T cell-specific TGF-β signaling, here we probed the temporal requirement of TGF-β in mucosal TRM formation. Using a murine model of reproductive tract infection, we found that restricting the availability of total or active TGF-β during naive T cell stage didn’t perturb CD8 T cells’ differentiation into TRM. However, abrogation of TGF-β signaling either during effector differentiation or early memory formation significantly reduced epithelial TRM differentiation. Even mature epithelial CD8 TRM cells relied on TGF-β signaling for their continued maintenance. Memory CD8 T cells generated in the absence of TGF-β signaling had altered functional profile after antigenic recall. Taken together, these suggest a stage-specific role of TGF-β in the formation of antiviral mucosal TRM formation with implications for improving vaccination and local immunotherapy approaches. Funding Sources R01 AI177704 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)