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

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. Con

SUBMITTER: Luckel C 

PROVIDER: S-EPMC6915776 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature