Differential requirements for TGF-β signaling and local antigen in CD8+ tissue resident memory T cell development in the upper versus lower respiratory tract 3811

Description CD8+ tissue-resident memory T cells (TRM) in the upper respiratory tract (URT) limit viral replication and prevent spread to the lower respiratory tract (LRT), where infection often causes significant morbidity and mortality. Using mouse models of intranasal and intraperitoneal vaccination, we show that URT CD8+ TRM can develop without local respiratory antigen, a feature distinguishing them from their LRT counterparts. Our findings reveal that IL-15 signaling and CD4 help, which are critical for LRT CD8+ TRM formation, are also dispensable for URT CD8+ TRM development in the absence of local antigen. However, we found that TGF-β signaling is essential for URT CD8+ TRM formation under these conditions, as conditional deletion of the TGF-β receptor prevents their development. Notably, the requirement of TGF-β signaling for URT CD8+ TRM development is abrogated when local antigen is present. To further dissect the mechanisms underlying these differences, we performed single-cell RNA sequencing to assess transcriptional programs driving URT and LRT CD8+ TRM formation under different combinations of local antigen availability and TGF-β signaling. Our work highlights key differences in the mechanisms that regulate CD8+ TRM development in distinct areas of the respiratory tract, offering valuable insights for T-cell-based vaccine strategies targeting respiratory viruses. Funding Sources Supported by NIH F31 HL176090 and NIH R35 HL150803. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)