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

产生IL-17的CD8+ T细胞（Tc17 cells）与多发性硬化（multiple sclerosis, MS）的发病机制密切相关，因此是颇具潜力的治疗靶点。本研究发现，作为多发性硬化一线治疗药物的富马酸二甲酯（dimethyl fumarate, DMF），可通过谷胱甘肽耗竭在小鼠Tc17细胞中上调活性氧（reactive oxygen species, ROS）水平，进而抑制IL-17的产生，并使Tc17细胞向细胞毒性T淋巴细胞（cytotoxic T lymphocyte, CTL）特征谱型转化。富马酸二甲酯可增强PI3K-AKT-FOXO1-T-bet及STAT5信号通路，致使Il17基因位点的组蛋白呈现受限的许可性修饰状态。T-bet缺陷、抑制PI3K-AKT通路、STAT5通路或组蛋白去乙酰化酶，均可阻断富马酸二甲酯-活性氧介导的IL-17抑制效应。在应答稳定的多发性硬化患者中，富马酸二甲酯可抑制CD8+ T细胞产生IL-17，并促使Tc17细胞向CTL特征谱型转化，同时伴随ROS、PI3K-AKT-FOXO1信号通路的活化增强，表明跨物种的调控机制具有一致性。相应地，在多发性硬化小鼠模型中，富马酸二甲酯可削弱Tc17细胞的致脑炎活性。本研究揭示了一条由富马酸二甲酯-活性氧-AKT介导的信号通路，该通路可选择性调控Tc17细胞的命运以改善多发性硬化病情，从而为开发特异性治疗的标志物与靶点提供了新方向。
实验整体设计：采集人体血液中的CD8+记忆性T细胞