期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 14, 期 640, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abl6058
关键词
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资金
- Swiss National Science Foundation [310030B_201271, 310030_185321]
- ERC [865026]
- Deutsche Forschungsgemeinschaft (DFG
- German Research Foundation) [408885537 B01, Sta 1389/5-1, TRR274/1]
- DFG under Germany's Excellence Strategy [EXC 2067/1-390729940]
- Swiss National Science Foundation (SNF) [310030B_201271, 310030_185321] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [865026] Funding Source: European Research Council (ERC)
The study reveals that tissue-resident memory T cells (T-RM) may initiate CNS inflammation and immunopathology in chronic inflammatory diseases of the central nervous system (CNS), independent of circulating CD8(+) T cells. In the absence of CD4(+) T cells, CD8(+) T cells fail to expand and differentiate into terminal effectors. This sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.
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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