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各种病原体。他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。为了实现这些不同的任务，免疫系统依赖于T细胞增殖、分化和谱系定型的复杂系统。因此，理解本质上调节单个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获得性免疫的重要内在调节因子。淋巴细胞代谢状态的紊乱可以改变T效应细胞/辅助细胞功能、记忆T细胞生成和自身耐受。对人类淋巴细胞的早期研究表明，促有丝分裂信号导致从头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，似乎是淋巴细胞有效生长所必需的。重要的是，脂肪生成程序的抑制降低了活化淋巴细胞的DNA合成和增殖能力。迄今为止，这些惊人的观察结果背后的分子机制仍然不确定。在本申请中，我们测试了以下假设：固醇反应元件结合蛋白（SREBP 1和2），脂质生物合成和稳态的关键转录调节因子，在将抗原受体信号传导与脂质代谢、细胞周期进展和T细胞命运/功能联系起来方面发挥关键作用。我们的目标是：1）确定调节SREBP活性和抗原受体下游的从头脂肪生成的信号传导途径; 2）检验SREBP信号传导调节活化T细胞中的细胞周期进程的假设;和3）检验SREBP调节CD 8 T细胞应答和免疫的假设。拟议的研究检查了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串扰的理解。这些研究将为更好地理解快速分裂的造血细胞和免疫细胞的脂质代谢、增殖和分化之间的关系提供基础。 公共卫生相关性：免疫学的一个重要目标是阐明调节抗原特异性免疫和自身免疫的机制。本提案中概述的实验将我们对T细胞免疫生物学的理解与目前关于分子脂质代谢的想法结合起来。这些研究将确定脂质代谢的转录调控对宿主防御和自身耐受的相对重要性，以及阐明抗原受体下游的信号通路，协调淋巴细胞的脂肪生成程序。此外，这些研究将为更好地理解脂质代谢程序对其他快速增殖的正常组织和肿瘤组织的潜在影响提供基础。鉴于内源性脂质可以改变许多人类疾病，如血脂异常和动脉粥样硬化，我们的研究结果提出了一个有趣的可能性，分子代谢可能会影响获得性免疫反应在人类代谢疾病，如血脂异常，肥胖症，糖尿病和代谢综合征。

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. PUBLIC HEALTH RELEVANCE: An important goal of immunology is elucidating the mechanisms that regulate antigen-specific immunity and autoimmunity. The experiments outlined in this proposal integrate our understanding of T cell immunobiology with current ideas regarding molecular lipid metabolism. These studies will define the relative importance of transcriptional regulation of lipid metabolism on host defense and self-tolerance, as well as elucidate the signaling pathways downstream of the antigen receptor that coordinate the lipogenic program of lymphocytes. Moreover, these studies will provide a foundation for better understanding the potential influence of lipid metabolic programs on other rapidly proliferating normal and neoplastic tissue. Given that endogenous lipids can be altered in a number of human diseases, such as dyslipidemia and atherosclerosis, our results raise the interesting possibility that molecular metabolism may impact acquired immune responses in human metabolic diseases such as dyslipidemia, obesity, diabetes and metabolic syndrome.