Functionally divergent resident memory T cells localize to lung and lymph node following influenza infection 2220996

Abstract Introduction Resident memory T cells (TRM) mediate localized immunity in barrier tissues while central memory T cells (TCM) recirculate through lymphoid organs to surveil for reinfection. Although TRM are classically associated with peripheral non-lymphid tissues, they have also been identified within lymph nodes (LNRM) where mechanisms guiding their formation and their role during secondary pathogen encounters remain poorly understood. Moreover, functional distinctions between TCM, LNRM, and lung TRM (LungRM) have not been clearly defined. Methods Flow cytometry, immunofluorescent imaging, RNA+ATAC sequencing, cytotoxic assays Results Using longitudinal antibody labeling, we tracked the migration of T cells after influenza infection and demonstrate that CD69+CD103+ T cells in lymph nodes are bona fide resident. LNRM accumulate throughout lung-draining lymph nodes and are present within all LN compartments including, sub capsular sinus, T cell zone and germinal centers. LNRM formation is conserved across viral strains, antigen specificities, and precursor populations. Epigenetic and transcriptional profiling reveal that LNRM are uniquely poised for cytotoxicity whereas LungRM resemble exhausted cells with elevated expression of inhibitory receptors and increased chromatin accessibility at the Pdcd1 locus. Regulatory network analysis of transcription factors, combined with target gene expression and chromatin accessibility identified key gene networks differentiating TCM, LNRM and LungRM. Upon antigen re-encounter, LNRM produce more IFNγ, are more proliferative, and are more cytotoxic than LungRM. Conclusion These findings establish LNRM as a distinct and durable memory population bridging features of circulating and tissue-resident cells. Our results suggest that LNRM may play a previously unappreciated role in orchestrating local recall responses within secondary lymphoid organs and provide superior effector functions than LungRM. Funding Source Ludwig Center Postdoctoral Fellowship Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)