GSH-dependent regulation of IL-17-producing CD8+ T cells in autoimmune inflammation of the central nervous system

中枢神经系统自身免疫炎症中产生 IL-17 的 CD8 T 细胞的 GSH 依赖性调节

• 批准号: 414259009
• 负责人: Professorin Dr. Magdalena Huber
• 金额: --
• 依托单位: Institut für Systemimmunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414259009?language=en
• 关键词: GSH; dependent; regulation; IL; 17

T cell-mediated autoimmunity of the central nervous system (CNS) is initiated by the activation of T cells in the periphery. Subsequently, the effector T cells migrate into the target tissue to mediate inflammation. Thus, factors modifying early T cell activation affect the following disease outbreak. Antigen recognition associated signaling upregulates reactive oxygen species (ROS) production, which interfere with cellular response. Whereas high ROS concentrations cause death, low levels support T cell activation, indicating modulating effect of ROS on the activation outcome. The most important cellular ROS scavenger is glutathione (GSH), which loss impairs T cell metabolic reprogramming and expansion. However, the influence of a transient GSH depletion on the T cell fate is not known. Dimethyl fumarate (DMF), a drug approved for treatment of relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease of the CNS, has a transient GSH-depleting activity. Considering that effects of DMF on T cells are not exactly known, we seek to delineate the principal impact of GSH-depletion on the fate of Tc17 cells with relevance for MS. This investigation will give mechanistic insights how pro-oxidants impinge on IL-17-driven autoimmunity and potentially beyond.

中枢神经系统（CNS）的T细胞介导的自身免疫是由外周中的T细胞的活化引发的。随后，效应T细胞迁移到靶组织中以介导炎症。因此，修饰早期T细胞活化的因素影响随后的疾病爆发。抗原识别相关的信号传导上调活性氧（ROS）的产生，其干扰细胞应答。尽管高ROS浓度导致死亡，但低水平支持T细胞活化，表明ROS对活化结果的调节作用。最重要的细胞ROS清除剂是谷胱甘肽（GSH），其损失损害T细胞代谢重编程和扩增。然而，暂时GSH耗竭对T细胞命运的影响尚不清楚。富马酸二甲酯（DMF）是一种获批用于治疗复发缓解型多发性硬化症（RRMS）（一种T细胞介导的CNS自身免疫性疾病）的药物，具有一过性GSH耗竭活性。考虑到DMF对T细胞的影响尚不完全清楚，我们试图描述GSH耗竭对与MS相关的Tc 17细胞命运的主要影响。这项研究将提供促氧化剂如何影响IL-17驱动的自身免疫的机制见解。