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.
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