Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

利用 CD4 T 细胞亚群的代谢脆弱性来控制炎症性疾病

• 批准号: 9889950
• 负责人: Jeffrey C. Rathmell
• 金额: $ 38.93万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889950
• 关键词: Affect; Autoimmune Process; Biochemical Pathway; CD4 Positive T Lymphocytes; Carbon; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Chromatin; Crohn' s disease; Cues; Data; Dependence; Disease; Disease model; Epigenetic Process; Equilibrium; Eragrostis; FOXP3 gene; Gene Expression; Gene-Modified; Generations; Genetic Models; Glucose Transporter; Glutaminase; Glutamine; Glycolysis; Goals; Histones; IL17 gene; Immune; Immunity; Immunologics; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Ligands; Link; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methylation; Mitochondria; Modification; Mus; NADP; Oxidoreductase; Pathology; Pathway Analysis; Pathway interactions; Pharmacology; Play; Production; Reactive Oxygen Species; Receptor Signaling; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Resolution; Role; Signal Transduction; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Toll-like receptors; Transforming Growth Factor beta; Work; base; cytokine; effector T cell; flexibility; glucose uptake; histone methylation; histone modification; immunoregulation; in vivo; inhibitor/antagonist; metabolomics; novel; programs; response; therapeutic target

Inflammatory diseases are often caused by inappropriate responses of effector CD4 T cells (Teff). Th17 Teff are IL17-producing CD4 T cells that contribute to a variety of immune pathologies, including Inflammatory Bowel Disease (IBD). Regulatory T cells (Treg), in contrast, suppress Teff to protect from disease. A key therapeutic objective in efforts to shift the immunologic balance towards tolerance, therefore, is to selectively inhibit Teff and promote Treg. We have shown that Th17 and Treg cells utilize fundamentally different metabolic programs, with Th17 being reliant on glucose uptake and glycolysis while Treg are primarily reliant on mitochondrial pathways. In our efforts to better understand the metabolic demands of each subset that could be targeted to selectively modulate CD4 T cells in inflammatory diseases, we have found that cytokine and inflammatory signals that drive Th17 and Treg differentiation each play distinct roles in control of T cell metabolism. Further, these metabolic changes may influence T cell fate through modulation of reactive oxygen species (ROS) and epigenetic modifications of gene expression. We showed that while Th17 require the glucose transporter Glut1 and glycolysis, FoxP3 and the Treg-inducing cytokine TGFβ inhibit this pathway and Treg can suppress independent of Glut1. Treg are metabolically flexible, however, and Toll-like receptors (TLR) ligands can stimulate Treg to increase glycolysis but with reduced suppressive capacity and expression of FoxP3. To identify additional metabolic pathways that may provide new immune modulatory targets, we performed high-resolution non-targeted metabolomics and metabolic network analyses. These studies identified glutaminolysis and one carbon metabolism as selectively enriched in Th17 relative to Treg. Here we will test the roles of Glutaminase (GLS) in glutaminolysis and Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in and one carbon metabolism in Th17 and Treg. Treg did not require GLS, but Treg differentiation and stability were suppressed by MTHFD2. In contrast, we show that Th17 cells require both GLS, and MTHFD2. While glycolysis, glutaminolysis, and one carbon metabolism are linked and each modulate both ROS and epigenetic marks, mechanisms by which they affect Treg and Th17 cells, remain unknown. Our data have led to the hypothesis that regulation of these metabolic pathways is essential for Treg and Th17 cells through control of ROS and epigenetic methylation and that GLS or MTHFD2 will provide new immuno- modulatory targets for inflammatory diseases. We will: (1) Determine how Treg glycolysis and MTHFD2 are regulated by inflammatory cues to control Treg function and FoxP3 expression; (2) Test signals that regulate Th17 metabolism and ROS and epigenetic modifications as mechanisms by which Th17 cells require GLS and MTHFD2; (3) Establish the in vivo potential of GLS and MTHFD2 as therapeutic targets to enhance Treg and suppress Th17 cells in inflammation. These studies will establish the opportunity and mechanisms of glycolysis, GLS, and MTHFD2 to suppress Th17 and promote Treg function and stability.

炎症性疾病通常是由效应器CD4T细胞的不适当反应引起的。TH17 TEFF是产生IL17的CD4T细胞，有助于多种免疫病理，包括炎症 肠病(IBD)。相比之下，调节性T细胞(Treg)抑制TEFF以防止疾病。一把钥匙 因此，努力将免疫平衡转向耐受的治疗目标是选择性地 抑制TJeff，促进Treg。我们已经证明Th17和Treg细胞利用根本不同的新陈代谢 Th17依赖于葡萄糖摄取和糖酵解，而Treg主要依赖于 线粒体途径。在我们努力更好地了解每个子集的新陈代谢需求时， 针对炎症性疾病中CD4T细胞的选择性调节，我们发现细胞因子和 驱动Th17和Treg分化的炎症信号在T细胞控制中各自发挥不同的作用 新陈代谢。此外，这些代谢变化可能通过调节活性氧来影响T细胞的命运 物种(ROS)和基因表达的表观遗传修饰。我们表明，虽然Th17需要 葡萄糖转运蛋白Glut1和糖酵解、FoxP3和Treg诱导的细胞因子转化生长因子β抑制这一途径和 Treg可以独立于Glut1抑制。然而，Treg在代谢上是灵活的，Toll样受体(TLR) 配体可以刺激Treg增加糖酵解，但抑制能力和表达 Foxp3.为了确定可能提供新的免疫调节靶点的其他代谢途径，我们 进行高分辨率非靶向代谢组学和代谢网络分析。这些研究 发现谷氨酰胺分解和一个碳代谢相对于Treg选择性地富含在Th17中。在这里我们 将测试谷氨酰胺酶(GLS)在谷氨酰胺分解和亚甲基四氢叶酸脱氢酶2中的作用 (MTHFD2)in和Th17和Treg的一个碳代谢。Treg不需要GLS，但Treg需要区分 和稳定性被MTHFD2抑制。相反，我们发现Th17细胞既需要GLS，也需要GLS MTHFD2.而糖酵解、谷氨酰胺分解和一种碳代谢是联系在一起的，每一种都调节着这三种代谢。 ROS和表观遗传标记，它们影响Treg和Th17细胞的机制仍然未知。我们的数据 导致了对这些代谢途径的调节对Treg和Th17细胞至关重要的假说 通过控制ROS和表观遗传甲基化，GLS或MTHFD2将提供新的免疫- 炎症疾病的调节靶点。我们将：(1)确定Treg糖酵解和MTHFD2是如何 受炎症信号调节以控制Treg功能和FoxP3的表达；(2)检测调节信号 Th17新陈代谢、ROS和表观遗传修饰作为Th17细胞需要GLS和 MTHFD2；(3)建立GLS和MTHFD2的体内潜能作为治疗靶点，以增强Treg和 抑制炎症中的Th17细胞。这些研究将建立以下机会和机制 糖酵解、GLS和MTHFD2抑制Th17，促进Treg功能和稳定性。