期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13731-z
关键词
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资金
- Biogen [IIT-GER_BGT-13_10580]
- UKGM [10/2016]
- DFG [HU 1824/7-1]
- Fresenius Stiftung [2015_A232]
- GIF [I-1474-414.13/2018]
- e:Med [CAPSYS-FKZ01ZX1304E]
- JPIAMR Restrict-Pneumo-AMR [FKZ 01Kl1702]
- LOEWE Medical-RNomics [FKZ 519/03/00.001-(0003)]
- FNR-PRIDE [PRIDE/11012546/NEXTIMMUNE]
- German Federal Ministry of Education and Research [BMBF 01EO1003]
- Biogen
- FNR-ATTRACT [A14/BM/7632103]
- FNR-CORE [C15/BM/10355103]
- National Health and Medical Research Council (NHMRC)
- Sylvia and Charles Viertel Foundation
- [SFB/TR-128]
- [SFB/TR-156]
- [SFB/TR-84 C1]
IL-17-producing CD8(+) (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8(+) T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXo1-T-BET pathway, thereby limiting IL-17 and ROR gamma t expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.
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