Tissue-resident memory CD8 + T cells cooperate with CD4 + T cells to drive compartmentalized immunopathology in the CNS

Abstract

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (T RM ) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8 + T RM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8 + T RM . Subsequently, CD8 + T RM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8 + T cells. However, in the absence of CD4 + T cells, TCF-1 + CD8 + T RM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8 + T cells expressing TCF-1 that predominantly exhibited a T RM -like phenotype. Together, our study provides evidence for CD8 + T RM -driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions. T RM generated after resolved brain virus infection that cross-react with CNS-specific self-antigen orchestrate a compartmentalized autoimmune disease. A local contribution to CNS autoimmunity Aberrantly activated tissue-resident memory T cells (T RM ) have been shown to contribute to inflammatory conditions. Their role in the CNS remains unclear. Now, in two complementary studies, Vincenti et al. and Frieser et al. investigated the role of T RM in the CNS. Vincenti and colleagues reported that after viral brain infection, T RM triggered CNS inflammation, promoting autoimmune reactions in mice. Cells with T RM -like phenotype were also identified in brain tissue from patients with CNS autoimmune diseases. Frieser et al. used rodent models of CNS autoimmunity to show that pathogenic CD8 + T cells infiltrating the CNS adopted a T RM phenotype that contributes to the disease. The results suggest that targeting T RM can be effective in treating CNS autoimmune diseases.