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

TLDR

Tissue‑resident memory T cells persist at sites of prior infection, enhance pathogen clearance by recruiting circulating immune cells and providing bystander activation, and brain‑resident TRM undergo spontaneous homeostatic proliferation while remaining largely refractory to systemic immune cell depletion. The study characterizes the functioning of brain‑resident memory T cells in an animal model of viral infection. After viral reinfection, brain‑resident TRM rapidly acquire cytotoxic effector function and prevent fatal brain infection even in the absence of circulating CD8⁺ memory T cells; antigen presentation on MHC‑I is essential, engaging perforin‑ and IFN‑γ‑dependent mechanisms, thereby establishing bTRM as an organ‑autonomous defense system and a paradigm for self‑sufficient first‑line adaptive immunity.

Abstract

Tissue-resident memory T cells (TRM) 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 (bTRM) in an animal model of viral infection. bTRM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bTRM 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 bTRM-mediated protective immunity, which involved perforin- and IFN-γ–dependent effector mechanisms. These findings identify bTRM as an organ-autonomous defense system serving as a paradigm for TRM functioning as a self-sufficient first line of adaptive immunity.