细胞毒性T细胞
自身免疫
CD8型
生物
免疫学
神经炎症
T细胞
免疫系统
炎症
体外
遗传学
作者
David Frieser,Aurora Pignata,Leila Khajavi,Danielle Shlesinger,Carmen Gonzalez-Fierro,Xuan‐Hung Nguyen,Alexander Yermanos,Doron Merkler,Romana Höftberger,Virginie Desestret,Katharina M Mair,Jan Bauer,Adele Preaudet,Roland Liblau
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-13
卷期号:14 (640)
被引量:50
标识
DOI:10.1126/scitranslmed.abl6157
摘要
The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+ T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+ T cells behind the blood-brain barrier adopt a characteristic TRM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+ T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+ T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+ T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+ T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+ T cells. Collectively, our results point to tissue-resident CD8+ T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.
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