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

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 RORgammat 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.

• Luckel, 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, F. C.
• Chao, Y. Y.
• Bertrams, W.
• Sexl, V.
• Schmeck, B.
• Bonetti, L.
• Grusdat, M.
• Lohoff, M.
• Zielinski, C. E.
• Zipp, F.
• Kallies, A.
• Brenner, D.
• Berger, M.
• Bopp, T.
• Tackenberg, B.
• Huber, M.