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) 的不当反应引起的。 Th1 和 Th17 Teff 被认为可引发多种免疫病理，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，努力将免疫平衡转向耐受性的一个关键治疗目标是选择性抑制 Teff 并促进 Treg。我们在这里展示了 Teff 和 Treg 利用 根本上不同的代谢程序，并提出确定每个子集的具体要求将为选择性调节炎症性疾病中的 CD4 T 细胞提供新方法。我们发现 Th1 和 Th17 细胞高表达葡萄糖转运蛋白 Glut1，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 (GAPDH)，并且糖酵解向乳酸的通量增加。相比之下，Treg 的 Glut1 和 PDHK1 表达较低，糖酵解通量有限，并且线粒体氧化基因表达和代谢产物丰富。重要的是，我们对 T 细胞特异性 Glut1 条件性缺失或 PDHK1 靶向的分析表明，糖酵解程序是体内 Teff 功能选择性需要的。在这里，我们建议测试其他代谢事件，这些事件通过高分辨率代谢组学质谱法鉴定为 Teff 中选择性调节的，并且可能为 Th1 和 Th17 提供脆弱性。相比之下，人们对 Treg 代谢的调节和要求知之甚少。然而，我们的数据表明，转录因子 FoxP3 促进 Treg 氧化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 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。基于 Teff 和 Treg 不同的代谢需求，我们假设关键的葡萄糖依赖性代谢物对 Teff 选择性至关重要，而糖酵解是 FoxP3 抑制以优化抑制能力的 Treg 脆弱性。为了测试这个模型，我们将：（1）识别和表征 Teff 规格和功能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扩张和预防IBD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 抑制剂并针对 Teff 代谢脆弱性的 MS 模型。这些研究将确定 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。