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: 9269283
• 负责人: Jeffrey C. Rathmell
• 金额: $ 37.91万
• 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: 2015-11-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269283
• 关键词: CD4 Positive T Lymphocytes; Cell Respiration; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Cues; Data; Dependence; Dependency; Disease; Down-Regulation; Equilibrium; Eragrostis; Event; Experimental Autoimmune Encephalomyelitis; FRAP1 gene; Gene Expression; Genetic; Glucose; Glucose Transporter; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Glycolysis Inhibition; Health; Immune; Immunity; Immunologics; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Lymphocyte; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Multiple Sclerosis; PDH kinase; Pathology; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Physiology; Regulation; Regulatory T-Lymphocyte; Resolution; Role; Signal Transduction; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transgenic Organisms; base; glucose metabolism; glucose uptake; immune function; in vivo; inhibitor/antagonist; metabolomics; migration; novel strategies; prevent; programs; response; transcription factor

 DESCRIPTION (provided by applicant): Inflammatory diseases are often caused by inappropriate responses of effector CD4 T cells (Teff). Th1 and Th17 Teff are recognized to drive a variety of immune pathologies, including Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). 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 show here that Teff and Treg utilize fundamentally different metabolic programs and propose that identifying specific requirements of each subset will provide a new approach to selectively modulate CD4 T cells in inflammatory disease. We have found Th1 and Th17 cells have high expression of the glucose transporter Glut1, and Th17 cells in particular have increased Pyruvate Dehydrogenase Kinase 1 (PDHK1), an enrichment of glycolytic intermediates up to Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), and elevated rates of glycolytic flux to lactate. Treg, in contrast, have low expression of Glut1 and PDHK1, limited glycolytic flux, and are instead enriched for mitochondrial oxidative gene expression and metabolites. Importantly, our analysis of T cell specific Glut1 conditional deletion or targeting of PDHK1 showed that a glycolytic program is selectively required for Teff function in vivo. Here we propose to test additional metabolic events that were identified by high- resolution metabolomics mass spectrometry as selectively regulated in Teff and that may provide vulnerabilities for Th1 and Th17. The regulation and requirements of Treg metabolism, in contrast, have been poorly understood. However, our data show that the transcription factor FoxP3 promotes Treg oxidative metabolism and suppresses the Phosphoinositide-3-kinase (PI3K)/Akt/mTOR pathway to lower Glut1 expression and glycolysis. Surprisingly, high rates of glycolysis reduced Treg suppressive capacity, as we found Glut1 transgenic Treg are functionally impaired and could not fully protect from IBD. Based on the distinct metabolic requirements of Teff and Treg, we hypothesize that key glucose-dependent metabolites are selectively essential for Teff while glycolysis is a Treg vulnerability that FoxP3 restrains to optimize suppressive capacity. To test this model we will: (1) Identify and characterize metabolites and metabolic pathways selectively required for Teff specification and function; (2) Determine how FoxP3 regulates metabolism and the role of glycolysis in Treg expansion and protection from IBD; (3) Establish how inhibition of glycolysis alters the Teff and Treg balance in a model of MS using selective PDHK1 inhibitors and targeting of Teff metabolic vulnerabilities. These studies will establish specific and selective metabolic demands of Teff and Treg physiology and identify pathways to modulate the Teff and Treg balance in inflammatory diseases.

 描述（由申请人提供）：炎症性疾病通常是由效应 CD4 T 细胞 (Teff) 的不当反应引起，Th1 和 Th17 Teff 被认为可驱动多种免疫病理，包括炎症性肠病 (IBD) 和多发性硬化症 (MS)。相比之下，调节性 T 细胞 (Treg) 会抑制 Teff 以预防疾病，因此，将免疫平衡转向耐受性的一个关键治疗目标是选择性地抑制 Teff。抑制 Teff 并促进 Treg 我们在此显示 Teff 和 Treg 利用。 我们发现 Th1 和 Th17 细胞具有葡萄糖转运蛋白 Glut1 的高表达，尤其是 Th17 细胞。丙酮酸脱氢酶激酶 1 (PDHK1) 增加，糖酵解中间体富集，直至 3-磷酸甘油醛脱氢酶相反，Glut1 和 PDHK1 的表达较低，糖酵解通量有限，而线粒体氧化基因表达和代谢物则丰富。重要的是，我们对 T 细胞特异性的分析。 Glut1 条件性删除或 PDHK1 靶向表明，糖酵解程序是体内 Teff 功能选择性需要的。在此，我们建议测试通过鉴定的其他代谢事件。相比之下，我们对 Teff 代谢的调节和要求知之甚少。代谢并抑制磷酸肌醇 3 激酶 (PI3K)/Akt/mTOR 通路，从而降低 Glut1 表达和糖酵解。令人惊讶的是，高糖酵解率降低了 Treg 的抑制能力，因为我们发现 Glut1 转基因 Treg 功能受损，无法完全预防 IBD。根据 Teff 和 Treg 不同的代谢要求，我们发现关键的葡萄糖依赖性代谢物是选择性必需的。对于 Teff，而糖酵解是 FoxP3 抑制的 Treg 漏洞，以优化抑制能力。为了测试该模型，我们将：（1）识别和表征 Teff 选择性所需的代谢物和代谢途径。 (2) 确定 FoxP3 如何调节代谢以及糖酵解在 Treg 扩增和 IBD 保护中的作用；(3) 确定糖酵解的抑制如何改变 Teff 和 Treg 平衡 使用选择性 PDHK1 抑制剂和针对 Teff 代谢脆弱性的 MS 模型这些研究将建立 Teff 和 Treg 生理学的特定和选择性代谢需求，并确定调节炎症性疾病中 Teff 和 Treg 平衡的途径。