Trophic Regulation in T Cell Homeostasis and Disease

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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.