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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该应用的重点是了解脂质重编程的分子机制 CD4 T 辅助细胞亚群的代谢，并评估甾醇代谢对 T 辅助细胞功能的影响。越来越多的证据表明 CD4 T 辅助细胞会迅速改变其代谢状态以响应 TCR 激活和细胞因子信号。这种重新编程对于匹配生物能和特定效应子功能的生物合成要求。一般来说，促炎性 CD4 T 细胞（例如 Th1 和 Th17) 获得强大的糖酵解程序，并将其代谢转变为合成代谢状态。相比之下，调节性 T 细胞在很大程度上依赖脂肪酸氧化和大分子分解代谢来满足其生物能和生物合成的要求。代谢编程中的这种区别似乎是至关重要的以保证 T 辅助细胞的正常功能。 T辅助细胞代谢状态的遗传或药理学操作可以减弱或加剧特定的效应器功能。例如，执行糖酵解程序会扰乱 Tregs 的抑制能力，并导致模型系统失去自我耐受性。相比之下，强制执行脂肪酸氧化代谢下调 Th1 和 Th17 细胞的促炎功能，从而减弱疾病的发病机制。这些观察结果得出这样一个概念：CD4 T 辅助细胞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，不同 T 辅助细胞的分子机制细胞获得必要的代谢程序仍然知之甚少。在最近的工作中，我们确定了甾醇调节元件结合蛋白（SREBP1 和 2）作为代谢重编程的关键调节因子 CD8 T 细胞。机制研究表明，SREBP 被 TCR 信号激活并驱动获取糖酵解和合成代谢。在缺乏 SREBP 活性的情况下，我们发现 CD8 T 细胞无法上调糖酵解通量和脂质合成，导致增殖能力差和减弱效应器反应。这些数据使我们推测 SREBP 将在调节 CD4 T 辅助细胞亚群分化和效应器功能。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 Th1 的体外分化和 Th17 细胞，但不影响调节性 T 细胞的诱导，也不影响 Foxp3 阳性 Tregs 的体内生成/稳态。因此，我们得出结论，SREBP 信号在在控制 T 辅助子集的平衡方面发挥着重要且先前未定义的作用。在这个应用程序中，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，并确定这些代谢是否途径控制自我耐受和自身免疫之间的平衡。