Journal article
IL-17 CD8 T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
C Lückel, F Picard, H Raifer, L Campos Carrascosa, A Guralnik, Y Zhang, M Klein, S Bittner, F Steffen, S Moos, F Marini, R Gloury, FC Kurschus, YY Chao, W Bertrams, V Sexl, B Schmeck, L Bonetti, M Grusdat, M Lohoff Show all
Nature Communications | NATURE PUBLISHING GROUP | Published : 2019
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..
View full abstractGrants
Awarded by Biogen
Funding Acknowledgements
We thank Dr. Finkernagel, Dr. Green, Dr. Dolga, Dr. Jastroch, Dr. Bauer, Dr. Garn, M.Sc. Vogel, B.Sc. Erlemann, B.Sc. Kolbl, 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-RNomicsFKZ 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.