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 CD4 T 细胞 (Teff) 的不当反应引起的。 Teff 是产生 IL17 的 CD4 T 细胞，可导致多种免疫病理，包括炎症 相比之下，肠道疾病 (IBD) 的调节性 T 细胞 (Treg) 则通过抑制 Teff 来预防疾病。 因此，努力将免疫平衡转向耐受性的治疗目标是选择性地 抑制 Teff 并促进 Treg 我们已经证明 Th17 和 Treg 细胞利用根本不同的代谢。 Th17 依赖于葡萄糖摄取和糖酵解，而 Treg 主要依赖于 我们努力更好地了解每个亚群的代谢需求。 靶向选择性调节炎症性疾病中的 CD4 T 细胞，我们发现细胞因子和 驱动 Th17 和 Treg 分化的炎症信号在 T 细胞的控制中各自发挥不同的作用 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。 我们发现，Th17 需要 ROS 和表观遗传修饰。 葡萄糖转运蛋白 Glut1 和糖酵解、FoxP3 和 Treg 诱导细胞因子 TGFβ 抑制该途径， Treg 可以独立于 Glut1 进行抑制，但 Treg 具有代谢灵活性，并且 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免疫调节靶点的其他代谢途径，我们 进行了高分辨率非靶向代谢组学和代谢网络分析。 相对于 Treg，我们确定了 Th17 中选择性富集的谷氨酰胺分解和一种碳代谢。 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)中和Th17和Treg中的一碳代谢不需要GLS，但Treg分化。 相比之下，我们发现 Th17 细胞需要 GLS 和 GLS。 MTHFD2。糖酵解、谷氨酰胺分解和一种碳代谢相互关联，并且各自调节两者。 ROS 和表观遗传标记以及它们影响 Treg 和 Th17 细胞的机制仍然未知。 得出这样的假设：这些代谢途径的调节对于 Treg 和 Th17 细胞至关重要 通过控制ROS和表观遗传甲基化，GLS或MTHFD2将提供新的免疫力- 我们将： (1) 确定 Treg 糖酵解和 MTHFD2 的作用。 (2) 调节的测试信号 Th17 代谢、ROS 和表观遗传修饰是 Th17 细胞需要 GLS 和 MTHFD2；(3) 确定 GLS 和 MTHFD2 作为增强 Treg 和 MTHFD2 的治疗靶点的体内潜力。 这些研究将确定抑制炎症中 Th17 细胞的机会和机制。 糖酵解、GLS 和 MTHFD2 抑制 Th17 并促进 Treg 功能和稳定性。