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

Christina Lückel, Felix Picard, Hartmann Raifer, Lucia Campos Carrascosa, Anna Guralnik, Yajuan Zhang, Matthias Klein, Stefan Bittner, Falk Steffen, Sonja Moos, Federico Marini, Renee Gloury, Florian C Kurschus, Ying-Yin Chao, Wilhelm Bertrams, Veronika Sexl, Bernd Schmeck, Lynn Bonetti, Melanie Grusdat, Michael LohoffChristina E Zielinski, Frauke Zipp, Axel Kallies, Dirk Brenner, Michael Berger, Tobias Bopp, Björn Tackenberg, Magdalena Huber

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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 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.

OriginalsprogEngelsk
Artikelnummer5722
TidsskriftNature Communications
Vol/bind10
Antal sider15
ISSN2041-1723
DOI
StatusUdgivet - 16. dec. 2019

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