RNAseq of (Dimethylfumarate)DMF-induced changes in human CD8+ memory cells

IL-17-producing CD8+ (Tc17)T cells are implicated in the pathogenesis of multiple sclerosis (MS), thereby representing a promising target for therapy. We found that dimethyl fumarate (DMF), a first-line medication for MS upregulated reactive oxygen species (ROS) by glutathione depletion in murine Tc17 cells, which limited IL-17 and diverted Tc17 cells towards cytotoxic T lymphocyte (CTL) signature. DMF enhanced PI3K-AKT-FOXO1-T-bet- as well as STAT5-signaling leading to restricted permissive histone state at the Il17 locus. T-bet-deficiency, inhibiting PI3K-AKT, STAT5 or histone deacetylases prevented DMF-ROS-mediated IL-17 suppression. In MS patients with stable response, DMF suppressed IL-17 production by CD8+ T-cells and triggered diversion from Tc17 towards CTL signature along with enriched ROS-, PI3K-AKT-FOXO1-signaling, demonstrating comparable regulation across species. Accordingly, in the mouse model for MS, DMF limited Tc17-encephalitogenicity. Our findings disclose DMF-ROS-AKT-driven pathway, which selectively modulates Tc17 fate to ameliorate MS, thus opening avenue to develop markers and targets for specific therapy. Overall design: CD8+ memory cells from human blood

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Lückel 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