Determining the Impact of SREBP on Adaptive Immunity

描述（由申请人提供）：T淋巴细胞的任务是确保宿主防御多种病原体。它们还必须保持对自身抗原的耐受性，以避免自身免疫和过敏性疾病。为了完成这些不同的任务，免疫系统依赖于一个复杂的T细胞增殖、分化和谱系承诺系统。因此，了解内在调节单个T细胞命运和功能的基本机制仍然是免疫生物学中的重要问题。越来越多的证据表明，代谢是淋巴细胞功能和适应性免疫的重要内在调节因子。淋巴细胞代谢状态的扰动可以改变T效应/辅助细胞功能、记忆T细胞生成和自我耐受。早期对人类淋巴细胞的研究表明，有丝分裂信号导致新生胆固醇和脂肪酸生物合成的快速增加。脂质生物合成程序先于DNA合成，似乎是有效淋巴细胞生长所必需的。重要的是，抑制脂肪生成程序会降低DNA合成和活化淋巴细胞的增殖能力。这些引人注目的观察结果背后的分子机制至今仍未明确。在本应用中，我们验证了甾醇反应元件结合蛋白（SREBP1和2），脂质生物合成和体内平衡的关键转录调节因子，在连接抗原受体信号与脂质代谢，细胞周期进展和T细胞命运/功能方面发挥关键作用的假设。我们的目标是：1)确定抗原受体下游调节SREBP活性和新生脂肪生成的信号通路；2)验证活化T细胞中SREBP信号调控细胞周期进程的假说；3)验证SREBP调控CD8 T细胞应答和免疫的假说。提出的研究检查淋巴细胞生物学的一个非常不了解和潜在的重要方面。我们期望这些研究将增加我们对代谢和适应性免疫之间的串扰的理解。这些研究将为更好地理解快速分裂的造血和免疫细胞的脂质代谢、增殖和分化之间的关系提供基础。

DESCRIPTION (provided by applicant): T lymphocytes are tasked with ensuring host defense against a diverse array of pathogens. They must also maintain tolerance to self-antigens to avoid autoimmunity and allergic disease. To achieve these disparate tasks, the immune system relies on a complex system of T cell proliferation, differentiation and lineage commitment. As such, understanding the fundamental mechanisms that intrinsically regulate the fate and function of an individual T cell remain important questions in immunobiology. Accumulating evidence indicates that metabolism is an important intrinsic regulator of lymphocyte function and adaptive immunity. Perturbations in the metabolic state of lymphocytes can alter T effector/helper cell function, memory T cell generation and self-tolerance. Early studies on human lymphocytes demonstrated that mitogenic signaling results in a rapid increase in de novo cholesterol and fatty acid biosynthesis. The lipid biosynthetic program precedes DNA synthesis and appears to be essential for efficient lymphocyte growth. Importantly, inhibition of the lipogenic program decreases DNA synthesis and proliferative capacity of activated lymphocytes. The molecular mechanisms underlying these striking observations have remained undefined to date. In this application, we test the hypothesis that the Sterol Response Element Binding Proteins (SREBP1 and 2), key transcriptional regulators of lipid biosynthesis and homeostasis, play a critical role in linking antigen receptor signaling with lipid metabolism, cell cycle progression and T cell fate/function. Our aims are: 1) To define the signaling pathways regulating SREBP activity and de novo lipogenesis downstream of the antigen receptor; 2) To test the hypothesis that SREBP signaling regulates cell cycle progression in activated T cells; and 3) To test the hypothesis that SREBP regulates CD8 T cell responses and immunity. The proposed studies examine a very poorly understood and potentially important aspect of lymphocyte biology. It is our expectation that these studies will increase our understanding of the crosstalk between metabolism and adaptive immunity. These studies will provide a foundation for better understanding the relationship between lipid metabolism, proliferation and differentiation in rapidly dividing hematopoietic and immune cells.