Temporal Dissection of TGF-β signaling reveals differential impact during female reproductive mucosal CD8 resident memory T cell differentiation

Resident memory CD8 T cell (TRM) development progresses through distinct stages beginning with activation of naive T cells into effectors in 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 TRM formation, but how TGF-β modulates these distinct stages of TRM differentiation is not known. Combining an epithelial organoid system and 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 the female reproductive tract (FRT) TRM formation. We found that restricting total or active TGF-β accessibility 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 CD103+ CD8 TRM cells relied on TGF-β signaling for their continued persistence. Memory CD8 T cells generated in the absence of TGF-β signaling exhibit reduced proliferation after antigenic recall. Taken together, these suggest a stage-specific role of TGF-β in antiviral FRT mucosal TRM formation with implications for improving vaccination approaches.