Lymph node resident memory T cells retain effector capabilities by evading lung resident memory dysfunction

Abstract Resident memory T cells (T RM ) mediate localized immunity in barrier tissues while central memory T cells (T CM ) recirculate through lymphoid organs to surveil for reinfection. Although T RM are classically associated with peripheral non-lymphoid tissues, they have also been identified within lymph nodes (LN RM ) where the mechanisms guiding their formation and functional differences remain poorly understood. Here we used longitudinal antibody labeling to track the migratory history of memory T cells after influenza infection and demonstrate that CD69 + CD103 + T cells are resident in the lymph node. LN RM accumulate evenly throughout the lung-draining lymph node and are present within all analyzed LN compartments including, the sub capsular sinus, T cell zone and germinal centers. Epigenetic and transcriptional profiling reveal that LN RM are uniquely poised for cytotoxicity whereas T RM in the lung (Lung RM ) 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 regulons differentiating T CM , LN RM and Lung RM states. Upon antigen re-encounter, LN RM are more proliferative, cytotoxic, and produce more IFNγ compared to Lung RM . Notably, we find that LN RM represent the most prevalent subset of memory T cells in human thoracic lymph nodes. These findings highlight functional heterogeneity in T RM and establish LN RM as a distinct and durable memory T cell population bridging features of circulating and tissue-resident cells.