Tissue-resident memory CD8 <sup>+</sup> T cells cooperate with CD4 <sup>+</sup> T cells to drive compartmentalized immunopathology in the CNS
Ilena Vincenti, Nicolas Pagé, Karin Steinbach, Alexander Yermanos, Sylvain Lemeille, Nicolás Gonzalo Núñez, Mario Kreutzfeldt, Bogna Klimek, Giovanni Di Liberto, Kristóf Égervári, Margot Piccinno, Ghazal Shammas, Alexandre Mariotte, Nicolas Fonta, Nicolas Liaudet, Danielle Shlesinger, Anna Rita Liuzzi, Ingrid Wagner, Cynthia Saadi, Christine Stadelmann, Sai T. Reddy, Burkhard Becher, Doron Merkler
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.