Dissecting functions of IL-23-dependent inflammatory Th17 cells

项目摘要 虽然产生IL-17的辅助性T细胞（Th 17）是自身免疫性疾病的主要致病因素， 功能多样性破坏了它们作为治疗自身免疫的预期靶点的潜力。th 17细胞 目前分为稳态和炎症亚群。注意到炎性Th 17细胞 可以是有益的（抗感染）和致病的（促自身免疫）。体内平衡和 已经广泛研究了炎性Th 17细胞。然而，如何解剖抗感染和亲- 炎性Th 17细胞的自身免疫功能在很大程度上是未知的。对这方面的知识有着迫切的需求 考虑到在接受一般炎症抑制剂的患者中观察到的严重感染和致死性结局， Th 17细胞（例如抗IL-23的抗体）。在此，炎性Th 17的自身免疫和抗感染亚群 首次通过实验区分细胞。这项资助的目的是阐明代谢 调节区分来自鼠模型和人的自身免疫和抗感染Th 17细胞 患者中心假设是自身免疫和抗感染Th 17亚群采用不同的丝氨酸 代谢程序其基本原理是，确定自身免疫和抗感染之间的差异 Th 17亚群将为新的治疗提供机会，其选择性比目前的治疗方法显著提高。 养生法中心假设将通过追求三个具体目标来检验：1）确定机制 用于调节自身免疫性Th 17亚群中的丝氨酸代谢; 2）确定丝氨酸 调节自身免疫性Th 17亚群的致病性;和3）确定转录和代谢 来自患有炎症性肠病（IBD）的患者的Th 17细胞的编程。在第一个目标下， 从鼠模型中回收的Th 17细胞将用于测量细胞内丝氨酸和Th 17的指标。 自身免疫致病性与丝氨酸代谢酶的调节。第二个目标，生物化学 方法和小鼠模型将被用来评估丝氨酸诱导的 Th 17细胞的细胞内甲基化和致病潜力。在第三个目标中，RNA-seq分析将是 以评估来自IBD患者的Th 17细胞的转录谱。这项研究提出， 应用是创新的，因为它关注免疫代谢调节，区分抗感染 和自身免疫性Th 17亚群，这是一种迄今尚未研究的机制。所提出的研究是有意义的 因为它有望为开发自身免疫性Th 17选择性治疗剂提供新的机会， 自身免疫性疾病这对于那些已经被感染或暴露的病人来说非常重要。 对某些病原体，如结核病，因为现有的Th 17抑制剂不能使用，由于风险， 降低患者对感染的控制。

Project Summary Although IL-17-producing T helper (Th17) cells are a major pathogenic contributor to autoimmune diseases, functional diversity undermines their potential as a prospective target for treating autoimmunity. Th17 cells are currently classified into homeostatic and inflammatory subpopulations. It was noted that inflammatory Th17 cells can be beneficial (anti-infection) and pathogenic (pro-autoimmunity). The distinction between homeostatic and inflammatory Th17 cells has been extensively studied. However, how to dissect the anti-infection and pro- autoimmunity functions of inflammatory Th17 cells is largely unknown. There is a critical need for this knowledge given serious infections and fatal outcomes observed in patients receiving general inhibitors of inflammatory Th17 cells (e.g. antibodies against IL-23). Herein, autoimmune and anti-infection subsets of inflammatory Th17 cells are for the first time distinguished experimentally. The objective of this grant is to elucidate the metabolic regulation discriminating autoimmune and anti-infection Th17 cells derived from murine models and human patients. The central hypothesis is that autoimmune and anti-infection Th17 subsets adopt distinct serine metabolic programming. The rationale is that determining the differences between autoimmune and anti-infection Th17 subsets will offer opportunities for novel therapeutics with substantially improved selectivity than the current regimens. The central hypothesis will be tested by pursuing three specific aims: 1) to determine the mechanism for regulating serine metabolism in the autoimmune Th17 subset; 2) to determine the mechanism by which serine regulates pathogenicity of the autoimmune Th17 subset; and 3) to determine the transcriptional and metabolic programming of Th17 cells from patients with inflammatory bowel disease (IBD). Under the first aim, autoimmune Th17 cells recovered from murine models will be used to measure intracellular serine and indicators of autoimmune pathogenicity with modulation of serine metabolic enzymes. For the second aim, biochemical approaches and murine models will be employed to evaluate the relationship between serine-induced intracellular methylation and pathogenic potential of Th17 cells. In the third aim, RNA-seq analysis will be performed to evaluate transcription profiles of Th17 cells from IBD patients. The research proposed in this application is innovative, because it focuses on the immunometabolic regulation discriminating anti-infection and autoimmune Th17 subsets, a heretofore-unexamined mechanism. The proposed research is significant because it is expected to provide novel opportunities to develop autoimmune Th17-selective therapeutics for autoimmune diseases. This would be extraordinarily important for patients that have been infected or exposed to certain pathogens, such as tuberculosis, since existing Th17 inhibitors cannot be used due to the risks of decreasing the patients’ control of the infection.