Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain T_RM Formation and Function

Tissue-resident memory (T_RM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 T_RM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, T_RM are transcriptionally and phenotypically distinct from central-memory T cells (T_CM) and effector-memory T cells (T_EM). Moreover, T_RM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, T_RM are governed by a contextual milieu that balances T_RM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain T_RM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)T_RM phenotype and function, and discuss the contribution of T_RM to promoting protective immune responses in situ while maintaining tissue homeostasis.