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.