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

Nat Commun. 2019 Dec 16;10(1):5722. doi: 10.1038/s41467-019-13731-z.

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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Dimethyl Fumarate / pharmacology*
  • Dimethyl Fumarate / therapeutic use
  • Encephalomyelitis, Autoimmune, Experimental / blood
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Humans
  • Immunosuppressive Agents
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Longitudinal Studies
  • Male
  • Mice
  • Middle Aged
  • Multiple Sclerosis / blood
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / immunology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Treatment Outcome
  • Young Adult

Substances

  • Immunosuppressive Agents
  • Interleukin-17
  • Dimethyl Fumarate