Understanding the influence of SREBP signaling on CD4 T helper cell biology

了解 SREBP 信号传导对 CD4 T 辅助细胞生物学的影响

• 批准号: 9178626
• 负责人: STEVEN J BENSINGER
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-10 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178626
• 关键词: Adopted; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding Proteins; Biochemical Pathway; Bioenergetics; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Catabolism; Cell Differentiation process; Cell Respiration; Cell physiology; Cells; Cellular biology; Cholesterol; Cholesterol Homeostasis; Colitis; Communities; Complex; Cytokine Signaling; Data; Development; Disease; Effector Cell; Equilibrium; Experimental Autoimmune Encephalomyelitis; Experimental Models; FOXP3 gene; Fatty Acids; Generations; Genetic; Genetic Transcription; Glycolysis; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; Immune system; In Vitro; Infectious Disease Immunology; Inflammatory; Lead; Ligands; Lipids; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Chaperones; Pathogenesis; Pathway interactions; Pharmacology; Play; Publishing; Regulatory Element; Regulatory T-Lymphocyte; Rheumatology; Role; SCAP protein; Self Tolerance; Shapes; Signal Transduction; Sterols; T memory cell; T-Lymphocyte; TCR Activation; Techniques; Testing; Work; adaptive immunity; attenuation; cholesterol biosynthesis; design; expectation; experimental study; fatty acid biosynthesis; fatty acid oxidation; genome-wide; immune function; in vivo; insight; lipid metabolism; macromolecule; mevalonate; pathogen; programs; response

PROJECT SUMMARY This application is focused on understanding the molecular mechanisms underlying reprogramming of lipid metabolism in CD4 T helper subsets, and assessing the impact of sterol metabolism on T helper cell function. Accumulating evidence indicates that CD4 T helper cells rapidly change their metabolic state in response to TCR activation and cytokine signals. This reprogramming is necessary to match the bioenergetic and biosynthetic requirements of specific effector functions. In general pro-inflammatory CD4 T cells (e.g., Th1 and Th17) acquire a robust glycolytic program, and shift their metabolism towards an anabolic state. In contrast, regulatory T cells are largely reliant on fatty acid oxidation and macromolecule catabolism to meet their bioenergetic and biosynthetic requirements. This distinction in metabolic programming appears to be essential for proper T helper cell function. Genetic or pharmacologic manipulation of a T helper cell's metabolic state can attenuate or exacerbate specific effector functions. For example, enforcing a glycolytic program perturbs the suppressive ability of Tregs, and results in a loss of self-tolerance in models systems. In contrast, enforcing fatty acid oxidative metabolism downregulates the pro-inflammatory function of Th1 and Th17 cells, thereby attenuating disease pathogenesis. These observations have led to the concept that a CD4 T helper cells metabolic state is a fundamental component of the effector program. Despite the clear importance of acquiring and maintaining the appropriate metabolic state, the molecular mechanisms underlying how distinct T helper cells acquire the requisite metabolic programs remain poorly understood. In recent work we have identified the sterol regulatory element binding proteins (SREBP1 and 2) as critical regulators of metabolic reprogramming in CD8 T cells. Mechanistic studies revealed that SREBPs are activated by TCR signals and drive acquisition of glycolysis and anabolic metabolism. In the absence of SREBP activity, we found that CD8 T cells were unable to upregulate glycolytic flux and synthesis of lipids, resulting in poor proliferative capacity and attenuated effector responses. These data have led us to hypothesize that SREBPs would play a critical function in regulating the CD4 T helper subset differentiation and effector function. In support of this hypothesis, we find in preliminary data that attenuation of the SREBP program selectively perturbs the in vitro differentiation of Th1 and Th17 cells, but does not influence induction of regulatory T cells, nor does it influence the generation/homeostasis of Foxp3-positive Tregs in vivo. Thus, we conclude that SREBP signaling plays an important and previously undefined role in controlling the balance of T helper subsets. In this application, we extend on these intriguing preliminary data and propose three integrated aims designed to elucidate the molecular mechanism(s) by which SREBPs influence T helper cell function, and determine if these metabolic pathways control the balance between self-tolerance and autoimmunity.

项目摘要 本申请的重点是了解脂质重编程的分子机制 本发明的目的是通过测定CD 4辅助性T细胞亚群中的固醇代谢，并评估固醇代谢对辅助性T细胞功能的影响来确定固醇代谢的水平。 越来越多的证据表明，CD 4 T辅助细胞迅速改变其代谢状态，以响应 TCR活化和细胞因子信号。这种重新编程是必要的，以匹配生物能量和 特定效应子功能的生物合成要求。通常，促炎性CD 4 T细胞（例如，th 1和 Th 17）获得一个强大的糖酵解程序，并将其代谢转向合成代谢状态。与此相反， 调节性T细胞在很大程度上依赖于脂肪酸氧化和大分子催化剂，以满足其 生物能量和生物合成需求。代谢编程中的这种区别似乎至关重要 辅助性T细胞正常功能T辅助细胞代谢状态的遗传或药理学操纵 可以减弱或加重特定的效应器功能。例如，强制执行糖酵解程序 抑制能力，并导致在模型系统的自我耐受性的损失。相反，强制执行 脂肪酸氧化代谢下调Th 1和Th 17细胞的促炎功能， 减弱疾病的发病机理。这些观察导致了CD 4 T辅助细胞的概念， 代谢状态是效应程序的基本组成部分。尽管收购的重要性显而易见 以及维持适当的代谢状态，这些分子机制是不同的T辅助细胞 细胞获得必需的代谢程序仍然知之甚少。在最近的工作中，我们发现 固醇调节元件结合蛋白（SREBP 1和2）作为代谢重编程的关键调节剂， CD 8 T细胞。机制研究表明，SREBP被TCR信号激活，并驱动细胞的获取。 糖酵解和合成代谢。在缺乏SREBP活性的情况下，我们发现CD 8 T细胞不能被激活。 上调糖酵解通量和脂质合成，导致增殖能力差， 效应子反应这些数据使我们假设SREBPs将在 调节CD 4辅助性T细胞亚群分化和效应子功能。为了支持这一假设，我们发现， 初步数据表明，SREBP程序的减弱选择性地干扰Th 1的体外分化 和Th 17细胞，但不影响调节性T细胞的诱导，也不影响 体内Foxp 3阳性T细胞的生成/稳态。因此，我们得出结论，SREBP信号通路发挥作用， 在控制辅助性T细胞亚群的平衡中起着重要的和以前未定义的作用。在本申请中，我们 扩展这些有趣的初步数据，并提出三个综合目标，旨在阐明 SREBP影响T辅助细胞功能的分子机制，并确定这些代谢产物是否 途径控制自身耐受和自身免疫之间的平衡。