Trophic Regulation in T Cell Homeostasis and Disease

描述（由申请人提供）：维持淋巴稳态对于避免自身免疫、淋巴瘤和免疫缺陷等疾病至关重要。我们建议研究一种新的T细胞稳态机制-通过调节葡萄糖摄取和葡萄糖转运体Glut1来控制营养使用或营养水平。淋巴细胞需要动态调节葡萄糖摄取，以使细胞在静息状态下存活，并在免疫反应中强劲生长和增殖。我们已经证明，葡萄糖摄取和代谢是可对T细胞存活和功能产生深远影响的调节事件。我们发现静息和活化T细胞的葡萄糖摄取在体外分别受到细胞因子白细胞介素7 （IL7）和白细胞介素2 （IL2）的严格调节。然而，调节Glut1所需的体内信号和信号机制以及葡萄糖摄取改变对T细胞大小、存活和功能的影响仍不确定。在这个应用中，我们建议解决这些问题，以建立免疫学和细胞代谢领域的桥梁。我们将：(1)通过将T细胞过继转移到IL7-/-宿主和在成熟T细胞中条件删除IL7R，确定IL7在调节Glut1表达和细胞内运输中的体内作用。(2)明确调节Glut1表达和细胞表面定位的信号机制。PI3K/Akt和Jak/STAT信号通路被IL7和IL2激活，这些通路将通过RNAi、转基因和敲除方法分析它们在细胞系和原代T细胞模型中调节Glut1的作用。(3)利用T细胞特异性Glut1转基因小鼠模型和体外Glut1 RNAi检测Glut1表达在T细胞发育和稳态中的作用。在Akt转基因小鼠中观察到的Glut1表达调节淋巴瘤和自身免疫的能力将被研究，以确定葡萄糖摄取改变如何影响疾病。总之，这些实验将确定调节T细胞葡萄糖摄取的信号和信号机制，并确定葡萄糖摄取在T细胞存活、激活和免疫系统疾病中的作用。

DESCRIPTION (provided by applicant): Maintenance of lymphoid homeostasis is critical to avert diseases such as autoimmunity, lymphoma, and immunodeficiency. We propose to study a novel mechanism of T cell homeostasis - control of nutrient usage, or trophic level, by regulation of glucose uptake and the glucose transporter, Glut1. Lymphocytes require dynamic regulation of glucose uptake to allow both cell survival in a resting state and robust growth and proliferation in immune responses. We have shown that glucose uptake and metabolism are regulated events that can have a profound impact on T cell survival and function. We show that glucose uptake in both resting and activated T cells is tightly regulated in vitro by the cytokines interleukin 7 (IL7) and interleukin 2 (IL2), respectively. The in vivo signals and signaling mechanisms required for regulation of Glut1 and the effects of altered glucose uptake on T cell size, survival, and function, however, remain uncertain. In this application, we propose to address these issues to bridge the fields of immunology and cellular metabolism. We will: (1) Determine the in vivo role of IL7 in regulation of Glut1 expression and intracellular trafficking by adoptive transfer of T cells into IL7-/- hosts and conditional deletion of IL7R in mature T cells. (2) Identify signaling mechanisms that regulate Glut1 expression and cell surface localization. The PI3K/Akt and Jak/STAT signaling pathways are activated by IL7 and IL2 and these pathways will be analyzed for their role in Glut1 regulation in cell line and primary T cell models using RNAi, transgenic, and knockout approaches. (3) Examine the role of Glut1 expression in T cell development and homeostasis using a T cell specific Glut1 transgenic mouse model and in vitro RNAi of Glut1. The ability of Glut1 expression to modulate lymphoma and autoimmunity observed in Akt transgenic mice will be investigated to determine how altered glucose uptake may affect disease. Together, these experiments will identify signals and signaling mechanisms that regulate T cell glucose uptake and determine the role of glucose uptake in T cell survival, activation, and diseases of the immune system.