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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...

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Main Authors: Lückel, Christina (Author) , Picard, Felix (Author) , Raifer, Hartmann (Author) , Campos Carrascosa, Lucia (Author) , Guralnik, Anna (Author) , Zhang, Yajuan (Author) , Klein, Matthias (Author) , Bittner, Stefan (Author) , Steffen, Falk (Author) , Moos, Sonja (Author) , Marini, Federico (Author) , Gloury, Renee (Author) , Kurschus, Florian (Author) , Chao, Ying-Yin (Author) , Bertrams, Wilhelm (Author) , Sexl, Veronika (Author) , Schmeck, Bernd (Author) , Bonetti, Lynn (Author) , Grusdat, Melanie (Author) , Lohoff, Michael (Author) , Zielinski, Christina E. (Author) , Zipp, Frauke (Author) , Kallies, Axel (Author) , Brenner, Dirk (Author) , Berger, Michael (Author) , Bopp, Tobias (Author) , Tackenberg, Björn (Author) , Huber, Magdalena (Author)
Format: Article (Journal)
Language:English
Published: Dec 16 2019
In: Nature Communications
Year: 2019, Volume: 10
ISSN:2041-1723
DOI:10.1038/s41467-019-13731-z
Online Access:Verlag, Volltext: https://doi.org/10.1038/s41467-019-13731-z
Verlag: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915776/
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Author Notes: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, Magdalena Huber
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Summary: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., Dimethyl fumarate (DMF) is a therapy for multiple sclerosis (MS) with undetermined mechanism of action. Here the authors find that clinical response to DMF associates with decrease in IL-17-producing CD8+ T cells (Tc17), delineate molecular pathways involved, and show that DMF suppresses Tc17 pathogenicity in a mouse model of MS.
Item Description:Gesehen am 04.03.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-019-13731-z

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