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

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 (TRM) represent a potentially important cellular player in this process. In this study, published in Science Translational Medicine, the group of Professor Doron Merkler investigated whether resting CD8+ TRM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. They demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+ TRM. Subsequently, CD8+ TRM 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+ TRM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, they found CD8+ T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, this study provides evidence for CD8+ TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.

This project was supported by the Swiss National Science Foundation (SNSF).

Implications

Tissue-resident memory T cells (TRM) are retained in tissues and have limited recirculation properties. When aberrantly activated, they contribute to inflammatory conditions, but little is known about their effect on the central nervous system (CNS). This article, first authored by Mrs Ilena Vincenti, member of  Professor Doron Merkler's team, reports that, following viral infection of the brain, TRM trigger neuroinflammation, promoting autoimmunity. Consequently, these cells may be critically involved in the formation and progression of lesions in autoimmune diseases of the CNS including multiple sclerosis and neuromyelitis optica spectrum disorders. Furthermore, TRM specific for different antigens may be involved in the pathogenesis of these lesions. This study provides new insights into the multistep process that can lead to neuroinflammation, shedding light on therapeutic approaches to combat chronic autoimmune diseases affecting the CNS.

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https://www.science.org/doi/10.1126/scitranslmed.abl6058

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