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

Lckel, C;Picard, F;Raifer, H;Campos Carrascosa, L;Guralnik, A;Zhang, Y;Klein, M;Bittner, S;Steffen, F;Moos, S;Marini, F;Gloury, R;Kurschus, FC;Chao, YY;Bertrams, W;Sexl, V;Schmeck, B;Bonetti, L;Grusdat, M;Lohoff, M;Zielinski, CE;Zipp, F;Kallies, A;Brenn

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 RORt 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.