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 Lohoff, Christina E. Zielinski, Frauke Zipp, Axel Kallies, Dirk Brenner, Michael Berger, Tobias Bopp, Björn Tackenberg and Magdalena Huber ()
Additional contact information
Christina Lückel: University of Marburg
Felix Picard: University of Marburg
Hartmann Raifer: University of Marburg
Lucia Campos Carrascosa: University of Marburg
Anna Guralnik: University of Marburg
Yajuan Zhang: University of Marburg
Matthias Klein: University Medical Center of the Johannes Gutenberg-University Mainz
Stefan Bittner: Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz
Falk Steffen: Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz
Sonja Moos: University Medical Center of the Johannes Gutenberg-University Mainz
Federico Marini: University Medical Center of the Johannes Gutenberg-University Mainz
Renee Gloury: University of Melbourne
Florian C. Kurschus: University Medical Center of the Johannes Gutenberg-University Mainz
Ying-Yin Chao: Technical University of Munich
Wilhelm Bertrams: Philipps-University Marburg, Member of the German Center for Lung Research (DZL)
Veronika Sexl: University of Veterinary Medicine Vienna
Bernd Schmeck: Philipps-University Marburg, Member of the German Center for Lung Research (DZL)
Lynn Bonetti: Luxembourg Institute of Health
Melanie Grusdat: Luxembourg Institute of Health
Michael Lohoff: University of Marburg
Christina E. Zielinski: Technical University of Munich
Frauke Zipp: Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz
Axel Kallies: University of Melbourne
Dirk Brenner: Luxembourg Institute of Health
Michael Berger: The Hebrew University
Tobias Bopp: University Medical Center of the Johannes Gutenberg-University Mainz
Björn Tackenberg: University of Marburg
Magdalena Huber: University of Marburg

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13731-z

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