Glucose Transport in Regulation of T Cell Activation and Inflammation

葡萄糖转运在 T 细胞激活和炎症调节中的作用

• 批准号: 8513581
• 负责人: Jeffrey C. Rathmell
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513581
• 关键词: Address; Affect; Animal Model; Aryl Hydrocarbon Receptor; Autoimmune Diseases; CD4 Positive T Lymphocytes; Cell Count; Cell Survival; Cell physiology; Cell surface; Cells; Data; Disease; Disease model; Elements; Eragrostis; Experimental Autoimmune Encephalomyelitis; Generations; Glucose; Glucose Transporter; Glycolysis; Goals; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Individual; Inflammation; Inflammatory; Knock-in Mouse; Knock-out; Lipids; Lymphocyte; Lymphocyte Activation; Measurement; Mediating; Metabolic; Metabolism; Modeling; Mus; Nuclear Hormone Receptors; Nutrient; Orphan; Pathway interactions; Peripheral; Phosphatidylinositols; Phosphotransferases; Play; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Rest; Role; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Transgenic Organisms; cell growth; cell type; estrogen-related receptor; glucose metabolism; glucose transport; glucose uptake; immune function; in vivo; innovation; novel; novel strategies; overexpression; oxidation; prevent; programs; receptor expression; trafficking

DESCRIPTION (provided by applicant): Lymphocyte activation must be controlled to allow proper immunity while preventing inappropriate inflammatory immune responses. One element that we have found critical to support T cell growth, proliferation, and effector function is glucoe metabolism. In particular, the glucose transporter Glut1 and glycolysis are upregulated upon activation and differentiation of CD4 T cells into effectors (Teff; Th1, Th2, and Th17 are considered here). Regulatory T cells (Treg), however, express lower levels of Glut1 and utilize lipid oxidation rather than glycolysis as a primary metabolic program. Importantly, cell metabolism must match the demands of each cell type and we have shown that the inhibition of glucose metabolism prevents specification and function of Teff, while Treg are preferentially generated if glucose is limiting or glycolysis is inhibited. Manipulation of CD4 T cell metabolism, therefore, may provide a new approach to modulate immunity and reduce Teff function in inflammatory and autoimmune diseases. It is unclear, however, how T cell metabolism is regulated and what impact disruption of glucose metabolism may have in vivo, where a wide variety of alternate nutrients are available to potentially replace glucose. To address this question we have studied the role and regulation of Glut1 using a unique set of animal models. Our preliminary data show that Glut1 overexpression leads to selective lymphoproliferation of Teff while conditional deletion of Glut1 in T cells reduces peripheral T cell numbers and effector function. Regulatory mechanisms that control Glut1 may therefore provide potential targets for immune suppression. Indeed, we have recently shown that the orphan nuclear hormone receptor Estrogen Related Receptor-? (ERR?) plays a key role in the glucose metabolism and function of Teff and may mediate the effects of the Aryl- hydrocarbon Receptor (AhR) on CD4 specification into Teff or Treg via regulation of Glut1. We hypothesize that glucose uptake and metabolism are central regulators of effector T cell generation and function and that Glut1 regulation through AhR and ERR? may provide a novel avenue for therapy of immune diseases. We propose to: (1) Determine the role of Glut1 in T cell metabolism, survival, and effector function; (2) Establish regulatory pathways that control Glut1 expression and cell surface trafficking in murine and human T cell activation and in CD4 subsets; and (3) Examine the regulation and role of Glut1 in Teff generation and function in experimental autoimmune encephalomyelitis and graft-vs.-host disease. These studies will apply our unique set of animal models in normal activation and in two inflammatory diseases to directly establish the role of Glut1 and glucose metabolism in immune function and regulation of Glut1 and glucose metabolism as potential modulators of immunological disease.

描述（由申请人提供）：必须控制淋巴细胞活化，以实现适当的免疫，同时防止不适当的炎症免疫反应。我们发现葡萄糖代谢是支持 T 细胞生长、增殖和效应器功能的关键元素之一。特别是，葡萄糖转运蛋白 Glut1 和糖酵解在 CD4 T 细胞激活和分化为效应细胞时上调（Teff；此处考虑 Th1、Th2 和 Th17）。然而，调节性 T 细胞 (Treg) 表达较低水平的 Glut1，并利用脂质氧化而不是糖酵解作为主要代谢程序。重要的是，细胞代谢必须符合每种细胞类型的需求，我们已经证明，葡萄糖代谢的抑制会阻碍 Teff 的规范和功能，而如果葡萄糖受到限制或糖酵解受到抑制，则优先生成 Treg。操纵 CD4 T 细胞代谢， 因此，可能提供一种在炎症和自身免疫性疾病中调节免疫和降低 Teff 功能的新方法。然而，目前尚不清楚 T 细胞代谢是如何调节的，以及葡萄糖代谢的破坏可能对体内产生什么影响，体内有多种替代营养素可以替代葡萄糖。为了解决这个问题，我们使用一组独特的动物模型研究了 Glut1 的作用和调节。我们的初步数据表明，Glut1 过度表达会导致 Teff 选择性淋巴增殖，而 T 细胞中 Glut1 的条件性缺失会减少外周 T 细胞数量和效应功能。因此，控制 Glut1 的调节机制可能为免疫抑制提供潜在的靶点。事实上，我们最近已经证明孤儿核激素受体雌激素相关受体-？ (ERR?) 在葡萄糖代谢和 Teff 功能中发挥关键作用，并可能通过调节 Glut1 介导芳基烃受体 (AhR) 对 CD4 规范化为 Teff 或 Treg 的影响。我们假设葡萄糖摄取和代谢是效应 T 细胞生成和功能的中心调节因子，而 Glut1 通过 AhR 和 ERR 进行调节？可能为免疫疾病的治疗提供新途径。我们建议：（1）确定Glut1在T细胞代谢、存活和效应功能中的作用； (2) 建立控制小鼠和人类T细胞激活和CD4亚群中Glut1表达和细胞表面运输的调控途径； (3) 检查 Glut1 在实验性自身免疫性脑脊髓炎和移植物抗宿主病中 Teff 生成和功能中的调节和作用。这些研究将应用我们独特的一组正常激活和两种炎症性疾病的动物模型，直接确定 Glut1 和葡萄糖代谢在免疫功能中的作用以及 Glut1 和葡萄糖代谢作为免疫疾病潜在调节剂的调节作用。