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: 10380136
• 负责人: Jeffrey C. Rathmell
• 金额: $ 38.13万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380136
• 关键词: Affect; Autoimmune; 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; 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.

炎症性疾病通常由效应CD 4 T细胞（Teff）的不适当反应引起。Th17 Teff是产生IL 17的CD 4 T细胞，其有助于多种免疫病理学，包括炎症性T细胞。 肠道疾病（IBD）。相反，调节性T细胞（Treg）抑制Teff以保护免受疾病。一个关键 因此，努力将免疫平衡向耐受性转移的治疗目标是选择性地 抑制Teff和促进Treg。我们已经表明，Th 17和Treg细胞利用根本不同的代谢途径， Th 17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代谢需求， 我们发现，细胞因子和T细胞在炎症性疾病中选择性调节CD 4 T细胞 驱动Th 17和Treg分化炎性信号各自在控制T细胞中发挥不同的作用 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。我们发现，虽然Th 17需要 葡萄糖转运蛋白Glut 1和糖酵解、FoxP 3和Treg诱导细胞因子TGFβ抑制该途径， Treg的抑制作用不依赖于Glut 1。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，但抑制能力和表达降低， 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 鉴定了相对于Treg，在Th 17中选择性地富集的氨解和一碳代谢。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。 （MTHFD 2）和Th 17和Treg中的一碳代谢。Treg不需要GLS，但需要Treg分化 和稳定性被MTHFD 2抑制。相反，我们发现Th 17细胞需要GLS， MTHFD 2.而糖酵解、氨解和一碳代谢是相互联系的，每一个都调节这两个过程。 ROS和表观遗传标记，它们影响Treg和Th 17细胞的机制仍然未知。我们的数据 已经导致了这样的假设，即这些代谢途径的调节对于Treg和Th 17细胞是必需的 通过控制ROS和表观遗传甲基化，GLS或MTHFD 2将提供新的免疫调节， 炎症性疾病的调节靶点。我们将：（1）确定Treg糖酵解和MTHFD 2是如何 受炎症因子调节以控制Treg功能和FoxP 3表达;（2）调节Treg功能和FoxP 3表达的测试信号。 Th 17代谢和ROS和表观遗传修饰作为Th 17细胞需要GLS和GLS的机制， （3）建立GLS和MTHFD 2作为治疗靶标以增强Treg和MTHFD 2的体内潜力; 抑制炎症中的Th 17细胞。这些研究将建立机会和机制， 糖酵解、GLS和MTHFD 2抑制Th 17并促进Treg功能和稳定性。