Peripherally induced brain tissue–resident memory CD8⁺ T cells mediate protection against CNS infection

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (T_RM) CD8⁺ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain T_RM cells. We show that peripheral infections generate antigen-specific CD8⁺ memory T cells in the brain that adopt a unique T_RM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain T_RM cells was revealed by intravital imaging. Notably, peripherally induced brain T_RM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain T_RM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.