Dissecting functions of IL-23-dependent inflammatory Th17 cells

项目摘要 尽管产生IL-17的T辅助细胞(Th17)是自身免疫性疾病的主要致病因素， 功能的多样性破坏了它们作为治疗自身免疫的潜在靶点的潜力。Th17细胞是 目前分为动态型和炎症型。人们注意到炎性Th17细胞 可以是有益的(抗感染)和致病的(促进自身免疫)。动态平衡和平衡之间的区别 炎性Th17细胞已被广泛研究。然而，如何解剖抗感染与促感染 炎症性Th17细胞的自身免疫功能在很大程度上是未知的。迫切需要这方面的知识。 考虑到接受一般炎症抑制剂治疗的患者的严重感染和致命后果 Th17细胞(如抗IL-23抗体)。在这里，炎症性Th17的自身免疫和抗感染亚群 细胞首次在实验上被区分开来。这项资助的目的是为了阐明新陈代谢 小鼠和人自身免疫和抗感染Th17细胞的分化调控 病人。中心假设是自身免疫和抗感染的Th17亚群采用不同的丝氨酸 新陈代谢编程。其基本原理是确定自身免疫和抗感染之间的差异 TH17亚群将为新疗法提供机会，其选择性比目前显著提高 养生法。中心假说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Th17亚群中的丝氨酸代谢；2)确定丝氨酸 调节自身免疫Th17亚群的致病性；以及3)确定转录和代谢 炎症性肠病患者Th17细胞的编程。在第一个目标下，自身免疫 从小鼠模型中回收的Th17细胞将用于测量细胞内丝氨酸和 调节丝氨酸代谢酶的自身免疫致病作用。对于第二个目标，生化 方法和小鼠模型将被用来评估丝氨酸诱导的 Th17细胞内甲基化与致病潜能。在第三个目标中，rna-seq分析将是 检测IBD患者Th17细胞的转录水平。这项研究中提出的 应用具有创新性，因为它侧重于区分抗感染的免疫代谢调节 以及自体免疫Th17亚群，这是一种迄今未被研究的机制。这项拟议的研究具有重要意义 因为它有望为开发自身免疫性Th17选择性疗法提供新的机会 自身免疫性疾病。这对于已经被感染或暴露的患者来说尤其重要。 对某些病原体，如结核病，因为现有的Th17抑制剂由于以下风险而无法使用 降低患者对感染的控制力。

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.