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IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
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IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
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Journal Article
IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
2019
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/21
/ 13/44
/ 13/95
/ 14
/ 38
/ 38/15
/ 38/61
/ 38/91
/ 631/250
/ 64
/ 64/110
/ 64/60
/ 96
/ 96/1
/ 96/109
/ 96/2
/ 96/31
/ 96/34
/ 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
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mice
/ Multiple Sclerosis - drug therapy
/ Multiple Sclerosis - immunology
/ Science
