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Nat Commun. 2019 Dec 16;10(1):5722. doi: 10.1038/s41467-019-13731-z.

IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis.

Author information

1
Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany.
2
Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
3
Core-Facility Flow Cytometry, University of Marburg, 35043, Marburg, Germany.
4
Laboratory of Gastroentrology and Hepatology, Erasmus MC University Medical Center, 3015 CE, Rotterdam, Netherlands.
5
Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
6
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
7
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
8
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
9
The Peter Doherty Institute for Infection and Immunity, Dept. of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, 3000, Australia.
10
The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade, Parkville, VIC, 3052, Australia.
11
Department of Dermatology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
12
Center for Translational Cancer Research TranslaTUM, Technical University of Munich, 81675, Munich, Germany.
13
German Center for Infection Research (DZIF), Munich, Germany.
14
Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), 35043, Marburg, Germany.
15
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
16
Dept. of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), 35043, Marburg, Germany.
17
Dept. of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg.
18
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
19
Odense Research Center for Anaphylaxis, Dept. of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, DK-5000, Denmark.
20
The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, 9112001, Israel.
21
Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
22
Center of Neuroimmunology, Dept. of Neurology, University of Marburg, 35043, Marburg, Germany.
23
Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany. magdalena.huber@staff.uni-marburg.de.

Abstract

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 RORγt 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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