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

Author

Listed:
  • Christina Lückel

    (University of Marburg
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • Felix Picard

    (University of Marburg)

  • Hartmann Raifer

    (University of Marburg
    University of Marburg)

  • Lucia Campos Carrascosa

    (University of Marburg
    Erasmus MC University Medical Center)

  • 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
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • Renee Gloury

    (University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Florian C. Kurschus

    (University Medical Center of the Johannes Gutenberg-University Mainz
    Heidelberg University Hospital)

  • Ying-Yin Chao

    (Technical University of Munich
    German Center for Infection Research (DZIF))

  • 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)
    University Medical Center Giessen and Marburg, 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
    German Center for Infection Research (DZIF))

  • Frauke Zipp

    (Department of Neurology at the University Medical Center of the Johannes Gutenberg-University Mainz)

  • Axel Kallies

    (University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Dirk Brenner

    (Luxembourg Institute of Health
    University of Luxembourg
    Odense University Hospital, University of Southern Denmark)

  • Michael Berger

    (The Hebrew University)

  • Tobias Bopp

    (University Medical Center of the Johannes Gutenberg-University Mainz
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • Björn Tackenberg

    (University of Marburg)

  • Magdalena Huber

    (University of Marburg)

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.

Suggested Citation

  • Christina Lückel & Felix Picard & Hartmann Raifer & Lucia Campos Carrascosa & Anna Guralnik & Yajuan Zhang & Matthias Klein & Stefan Bittner & Falk Steffen & Sonja Moos & Federico Marini & Renee Glour, 2019. "IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13731-z
    DOI: 10.1038/s41467-019-13731-z
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    Cited by:

    1. A.-M. Globig & A. V. Hipp & P. Otto-Mora & M. Heeg & L. S. Mayer & S. Ehl & H. Schwacha & M. Bewtra & V. Tomov & R. Thimme & P. Hasselblatt & B. Bengsch, 2022. "High-dimensional profiling reveals Tc17 cell enrichment in active Crohn’s disease and identifies a potentially targetable signature," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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