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.