Dimethyl fumarate suppresses Tc17 cell fate in autoimmunity via ROS accumulation

Dimethyl fumarate (DMF) is approved for treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory disease of the central nervous system (CNS) that is caused by autoreactive T cells. The effect mechanism of DMF is not fully elucidated so far; however, a preferential impact on...

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Bibliographic Details
Main Author: Lückel, Christina
Contributors: Huber, Magdalena (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:English
Published: Philipps-Universität Marburg 2018
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Summary:Dimethyl fumarate (DMF) is approved for treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory disease of the central nervous system (CNS) that is caused by autoreactive T cells. The effect mechanism of DMF is not fully elucidated so far; however, a preferential impact on CD8+ T cells was described. In the cerebrospinal fluid (CSF) of MS patients IL-17-producing CD8+ T (Tc17) cells are enriched. In addition, during experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), a co-pathogenic function of Tc17 was described. Hence, Tc17 cells crucially contribute to autoimmune processes in the CNS of men and mice. This study shows that DMF elevated reactive oxygen species (ROS) in CD4+ T (Th17) cells and Tc17 cells by glutathione depletion, resulting in IL-17 suppression particularly in Tc17 cells. Accordingly, IL-17 production by CD8+ but not by CD4+ T cells was reduced in DMF-treated MS patients and DMF application diminished Tc17 cell pathogenicity in EAE. Accumulated ROS shifts the Tc17 transcriptome towards a cytotoxic T lymphocyte (CTL)-like signature by enhancing IL-2 signalling including phosphoinositide-3-kinase (PI3K)/ protein kinase B (AKT) and signal transducer and activator of transcription (STAT)5 pathways. AKT deactivated forkhead-box-Protein O (FOXO)1 leading to the upregulation of the transcription factor T-box transcription factor TBX21 (T-bet), which in turn suppressed IL-17. The modified transcriptional network was accompanied by altered histone modifications at the Il17 locus. In line, T-bet-deficiency, inhibition of histone deacetylases (HDAC), PI3K/AKT or STAT5 partially prevented DMF-mediated suppression of Tc17 cells. Thus, this work provides mechanistic insights into the selective modulation of Tc17 cell differentiation by DMF-mediated upregulation of ROS and IL-2 signalling with relevance for Tc17-driven pathologies including MS and psoriasis.
Physical Description:105 Pages
DOI:10.17192/z2018.0330