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

December 16, 2019 By:
  • 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 FC
  • Chao YY
  • Bertrams W
  • Sexl V
  • Schmeck B
  • Bonetti L
  • Grusdat M
  • Lohoff M
  • Zielinski CE
  • Zipp F
  • Kallies A
  • Brenner D
  • Berger M
  • Bopp T
  • Tackenberg B
  • Huber M.

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.

2019 Dec. Nat Commun.10(1):5722.
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