[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Lückel, Christina; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany ; Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Picard, Felix ; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany
Raifer, Hartmann; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany ; Core-Facility Flow Cytometry, University of Marburg, 35043, Marburg, Germany
Campos Carrascosa, Lucia; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany ; Laboratory of Gastroentrology and Hepatology, Erasmus MC University Medical Center, 3015 CE, Rotterdam, Netherlands
Guralnik, Anna; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany
Zhang, Yajuan; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany
Klein, Matthias; Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Bittner, Stefan ; Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Steffen, Falk; Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Moos, Sonja; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Marini, Federico ; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany ; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Gloury, Renee; The Peter Doherty Institute for Infection and Immunity, Dept. of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, 3000, Australia ; The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade, Parkville, VIC, 3052, Australia
Kurschus, Florian C; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany ; Department of Dermatology, Heidelberg University Hospital, 69120, Heidelberg, Germany
Chao, Ying-Yin; Center for Translational Cancer Research TranslaTUM, Technical University of Munich, 81675, Munich, Germany ; German Center for Infection Research (DZIF), Munich, Germany
Bertrams, Wilhelm; 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
Sexl, Veronika; Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
Schmeck, Bernd; 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 ; 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
Bonetti, Lynn; Dept. of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg
Grusdat, Melanie; Dept. of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg
Lohoff, Michael; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany
Zielinski, Christina E; Center for Translational Cancer Research TranslaTUM, Technical University of Munich, 81675, Munich, Germany ; German Center for Infection Research (DZIF), Munich, Germany
Zipp, Frauke ; Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Kallies, Axel ; The Peter Doherty Institute for Infection and Immunity, Dept. of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, 3000, Australia ; The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade, Parkville, VIC, 3052, Australia
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Dept. of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Luxembourg ; Odense Research Center for Anaphylaxis, Dept. of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, DK-5000, Denmark
Berger, Michael ; The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, 9112001, Israel
Bopp, Tobias ; Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany ; Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany
Tackenberg, Björn; Center of Neuroimmunology, Dept. of Neurology, University of Marburg, 35043, Marburg, Germany
Huber, Magdalena; Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany. magdalena.huber@staff.uni-marburg.de
German-Israeli Foundation for Scientific Research and Development Deutsche Forschungsgemeinschaft Else Kröner-Fresenius-Stiftung
Funding text :
We thank Dr. Finkernagel, Dr. Green, Dr. Dolga, Dr. Jastroch, Dr. Bauer, Dr. Garn, M. Sc. Vogel, B. Sc. Erlemann, B. Sc. Kölbl, M. Sc. Ruhe, Mr. Happel, B. Sc. Girschik for experimental support. This work was supported by Biogen IIT-GER_BGT-13_10580 (M. H.;B.T.), UKGM 10/2016 (M.H.), DFG HU 1824/7-1 (M.H.), Fresenius Stiftung, 2015_A232 (M.H.), GIF I-1474-414.13/2018 M.H., M.B.), SFB/TR-128 (S.B.,F.Z.,F.C.K., T.B.), and SFB/TR-156 (F.C.K.); e:Med CAPSYS-FKZ01ZX1304E, JPIAMR Restrict-Pneumo-AMR - FKZ 01Kl1702 (B.S), SFB/TR-84 C1 (B.S), LOEWE Medical-RNomics-FKZ 519/03/00.001-(0003) (B.S); D.B. and L.B. are funded by FNR-PRIDE (PRIDE/ 11012546/NEXTIMMUNE), FNR-ATTRACT (A14/BM/7632103) and FNR-CORE (C15/BM/10355103); National Health and Medical Research Council (NHMRC) and Sylvia and Charles Viertel Foundation (A.K.); German Federal Ministry of Education and Research (BMBF 01EO1003). This study was investigator initiated and funded by an unrestricted grant of Biogen, the manufacturer of dimethyl fumarate (Tecfidera). Biogen was not involved in data storage, data analysis or data interpretation. Biogen was informed about the results and was neither involved in the submission, nor the publication of the paper.
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