Glucose Transport in Regulation of T Cell Activation and Inflammation

描述(由申请人提供)：必须控制淋巴细胞的激活，以允许适当的免疫，同时防止不适当的炎症免疫反应。我们已经发现对支持T细胞生长、增殖和效应器功能至关重要的一个因素是糖代谢。特别是，葡萄糖转运蛋白Glut1和糖酵解在CD4T细胞激活和分化为效应器时上调(这里考虑的是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，细胞代谢必须与每一种细胞类型的需求相匹配，我们已经证明，抑制葡萄糖代谢会阻止Tef的指定和功能，而如果葡萄糖受到限制或糖酵解受到抑制，则会优先产生Treg。对CD4T细胞代谢的调控， 因此，可能为炎症性疾病和自身免疫性疾病的免疫调节和降低T细胞因子功能提供新的途径。然而，目前尚不清楚T细胞代谢是如何调节的，以及葡萄糖代谢的中断在体内可能会产生什么影响，在体内，有各种各样的替代营养物质可以潜在地取代葡萄糖。为了解决这个问题，我们使用了一套独特的动物模型来研究Glut1的作用和调控。我们的初步数据显示，Glut1的过度表达导致T细胞的选择性淋巴增殖，而T细胞中Glut1的有条件缺失减少了外周T细胞的数量和效应器功能。因此，控制Glut1的调节机制可能为免疫抑制提供潜在的靶点。的确，我们最近已经表明，孤儿核激素受体与雌激素相关的受体？(错误？)在糖代谢和糖代谢功能中起关键作用，并可能通过调节Glut1介导芳香烃受体(AhR)对TJeff或Treg的调节作用。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，Glut1通过AhR和Err？可能为免疫性疾病的治疗提供一条新的途径。我们建议：(1)确定Glut1在T细胞代谢、存活和效应器功能中的作用；(2)建立在小鼠和人类T细胞激活和CD4亚群中控制Glut1表达和细胞表面转运的调节通路；以及(3)研究Glut1在实验性自身免疫性脑脊髓炎和移植物抗宿主病的T细胞生成和功能中的调节和作用。这些研究将在正常激活和两种炎症性疾病中应用我们独特的一套动物模型，以直接确定Glut1和葡萄糖代谢在免疫功能中的作用以及作为免疫疾病潜在调节因子的Glut1和葡萄糖代谢的调节。

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.