Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany.
Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
Nat Commun. 2019 Dec 16;10(1):5722. doi: 10.1038/s41467-019-13731-z.
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.
IL-17 产生的 CD8（Tc17）细胞在多发性硬化症（MS）患者的活动性病变中富集，表明其在自身免疫发病机制中的作用。在这里，我们表明，二甲基富马酸（DMF）的改善，一种机制上难以捉摸的药物，与 Tc17 细胞的抑制有关。DMF 治疗导致 Tc17 的频率降低，与 Th17 细胞相反，并且 RORC 与 TBX21 的比率降低，同时在来自 MS 患者的 CD8 T 细胞中向细胞毒性 T 淋巴细胞基因表达特征转变。在机制上，DMF 增强了 PI3K-AKT-FOXO1-T-BET 途径，从而以谷胱甘肽依赖的方式限制了 IL-17 和 RORγt 的表达以及 STAT5 信号传导。这导致 Il17 基因座的染色质重塑。因此，在小鼠中缺乏 T-BET 或抑制 PI3K-AKT、STAT5 或活性氧可以防止 DMF 介导的 Tc17 抑制。总体而言，我们的数据揭示了 DMF-AKT-T-BET 驱动的免疫调节，并提出了 MS 及其他疾病的潜在治疗靶点。
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