Glucose Transport in Regulation of T Cell Activation and Inflammation

描述（由申请方提供）：必须控制淋巴细胞活化，以获得适当的免疫力，同时防止不适当的炎症免疫反应。我们发现支持T细胞生长、增殖和效应子功能的关键因素之一是葡萄糖代谢。特别是，葡萄糖转运蛋白Glut 1和糖酵解在CD 4 T细胞活化和分化为效应子（Teff; Th 1，Th 2和Th 17在这里被考虑）时上调。然而，调节性T细胞（Treg）表达较低水平的Glut 1，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，细胞代谢必须与每种细胞类型的需求相匹配，并且我们已经表明，葡萄糖代谢的抑制阻止了Teff的特化和功能，而如果葡萄糖受限或糖酵解被抑制，则优先产生Treg。操纵CD 4 T细胞代谢， 因此，可能提供一种新的方法来调节免疫和减少Teff功能的炎症和自身免疫性疾病。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在体内产生什么影响，其中有各种各样的替代营养素可用于潜在地替代葡萄糖。为了解决这个问题，我们使用一组独特的动物模型研究了Glut 1的作用和调节。我们的初步数据表明，Glut 1过表达导致Teff的选择性淋巴细胞增殖，而T细胞中Glut 1的条件性缺失降低外周T细胞数量和效应功能。因此，控制Glut 1的调节机制可能为免疫抑制提供潜在的靶点。事实上，我们最近已经表明，孤儿核激素受体雌激素相关受体-？(ERR?)在Teff的葡萄糖代谢和功能中起关键作用，并且可以介导芳基烃受体（AhR）通过调节Glut 1对CD 4特化为Teff或Treg的作用。我们假设葡萄糖的摄取和代谢是效应T细胞产生和功能的中心调节因子，Glut 1通过AhR和ERR调节？可能为免疫性疾病的治疗提供新的途径。我们建议：（1）确定Glut 1在T细胞代谢、存活和效应子功能中的作用;（2）建立控制Glut 1在鼠和人T细胞活化和CD 4亚群中表达和细胞表面运输的调节途径;和（3）检查Glut 1在实验性自身免疫性脑脊髓炎和移植物抗-T细胞中Teff产生和功能中的调节和作用。宿主疾病这些研究将应用我们独特的一组动物模型在正常激活和两种炎症性疾病中直接建立Glut 1和葡萄糖代谢在免疫功能中的作用，以及Glut 1和葡萄糖代谢作为免疫疾病的潜在调节剂的调节作用。

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.