Zeitschriftenaufsatz
|
2019
IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
Autor:in
Lueckel, C.; Picard, Felix; Raifer, Hartmann; Carrascosa, Lucia Campos; Guralnik, Anna; Zhang, Yajuan; Klein, Matthias; Bittner, Stefan; Steffen, Falk; Moos, S.; Marini, Federico; Gloury, R. E.; Kurschus, Florian; chao, ying; Bertrams, Wilhelm; Sexl, Veronika; Schmeck, Bernd; Bonetti, Lynn; Grusdat, Melanie; Lohoff, Michael; Zielinski, Christina; Zipp, Frauke; Kallies, Axel; Brenner, Dirk; Berger, Michael; Bopp, Tobias; Tackenberg, Bjoern; Huber, Magdalena
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
Adolescent; Adult; Animals; CD8-Positive T-Lymphocytesdrug effectsimmunologymetabolism; Dimethyl Fumaratepharmacologytherapeutic use; Encephalomyelitis, Autoimmune, Experimentalblooddrug therapyimmunology; Female; Humans; Immunosuppressive Agents; Interleukin-17immunologymetabolism; Longitudinal Studies; Male; Mice; Middle Aged; Multiple Sclerosisblooddrug therapyimmunology; Th17 Cellsdrug effectsimmunology; Treatment Outcome; Young Adult
Dokumententyp
Originalarbeit
CC Lizenz
CCBY
Open Access Type
Gold
ISSN/eISSN
2041-1723 -
10.1038/s41467-019-13731-z
WoS ID
PubMed ID