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) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8 T 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. Subsequently, CD8 T 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 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-like phenotype. Together, our study provides evidence for CD8 T-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.