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

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.