Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection

Tissue-resident memory T cells (T_RM) persist at sites of prior infection and have been shown to enhance pathogen clearance by recruiting circulating immune cells and providing bystander activation. Here, we characterize the functioning of brain-resident memory T cells (bT_RM) in an animal model of viral infection. bT_RM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bT_RM rapidly acquired cytotoxic effector function and prevented fatal brain infection, even in the absence of circulating CD8⁺ memory T cells. Presentation of cognate antigen on MHC-I was essential for bT_RM-mediated protective immunity, which involved perforin- and IFN-γ-dependent effector mechanisms. These findings identify bT_RM as an organ-autonomous defense system serving as a paradigm for T_RM functioning as a self-sufficient first line of adaptive immunity.