TY - JOUR
T1 - IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
AU - Lückel, Christina
AU - Picard, Felix
AU - Raifer, Hartmann
AU - Campos Carrascosa, Lucia
AU - Guralnik, Anna
AU - Zhang, Yajuan
AU - Klein, Matthias
AU - Bittner, Stefan
AU - Steffen, Falk
AU - Moos, Sonja
AU - Marini, Federico
AU - Gloury, Renee
AU - Kurschus, Florian C.
AU - Chao, Ying Yin
AU - Bertrams, Wilhelm
AU - Sexl, Veronika
AU - Schmeck, Bernd
AU - Bonetti, Lynn
AU - Grusdat, Melanie
AU - Lohoff, Michael
AU - Zielinski, Christina E.
AU - Zipp, Frauke
AU - Kallies, Axel
AU - Brenner, Dirk
AU - Berger, Michael
AU - Bopp, Tobias
AU - Tackenberg, Björn
AU - Huber, Magdalena
N1 - Funding Information:
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.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076623980&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/31844089
U2 - 10.1038/s41467-019-13731-z
DO - 10.1038/s41467-019-13731-z
M3 - Article
C2 - 31844089
AN - SCOPUS:85076623980
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5722
ER -