Brain-Resident Memory T Cells: Cellular Mechanisms and Engineering Perspectives in Neuroimmune Surveillance

Abstract Purpose Brain-resident tissue-resident memory T cells (bTRM) form a stable, locally adapted memory T-cell compartment that challenges traditional concepts of central nervous system (CNS) immune privilege. This review summarizes the mechanisms governing bTRM residency and function and explores their relevance to CNS disease and therapeutic engineering. Methods We integrate evidence on bTRM phenotype, development, niche localization, transcriptional and epigenetic regulation, metabolic adaptation, and mechanobiology, with emphasis on mechanisms unique to the CNS. Results bTRM persistence is coordinated by tissue-retention programs, including the CD69/S1PR1 axis, transcriptional regulators such as Runx3, Hobit, and Blimp-1, metabolic adaptations including lipid utilization and oxidative phosphorylation, and signals from parenchymal, perivascular, meningeal, and other CNS border niches. Functionally, bTRM provide rapid antiviral protection and contribute to tumor immune surveillance, but may also sustain chronic neuroinflammation and autoimmunity. Their capacity for durable residency and adaptation to restrictive tissue environments further provides principles for engineering therapeutic T cells with improved persistence and local function. Conclusions bTRM represent a specialized component of CNS immunity with context-dependent protective and pathogenic functions. Defining the molecular, metabolic, spatial, and biomechanical mechanisms governing their persistence may enable targeted modulation of CNS immunity and inform the design of more durable cellular therapies.