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

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.