Mitochondria regulate adaptive immunity

线粒体调节适应性免疫

• 批准号: 10462617
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 39.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462617
• 关键词: Back; Binding Sites; CD8-Positive T-Lymphocytes; Cell Maintenance; Cell Respiration; Cell physiology; Cells; Chromatin; Citric Acid Cycle; Complex; DNA; DNA Methylation; DNA Modification Process; Data; Electron Transport; Electron Transport Complex III; Enzymes; Exhibits; FOXP3 gene; Generations; Genetic; Glycolysis; Grant; Histones; Immunity; Immunology; In Vitro; Knowledge; Maintenance; Mediator of activation protein; Memory; Metabolic; Metabolism; Mitochondria; Mus; Nature; Oxidative Phosphorylation; Oxygen Consumption; Pathogenicity; Phase; Phenotype; Production; Proliferating; Reactive Oxygen Species; Reagent; Regulatory T-Lymphocyte; Resolution; Role; Succinates; T-Cell Activation; T-Lymphocyte; Testing; Transcriptional Regulation; adaptive immune response; adaptive immunity; base; experimental study; glucose uptake; histone methylation; immune function; in vivo; migration; mitochondrial metabolism; novel; tool; transcription factor

Abstract T cells are major mediators of adaptive immune responses and resolution. Previously, we found that activated T cells also increase their rate of mitochondrial oxygen consumption; and that in the absence of a critical subunit of complex III within the electron transport chain, T cells failed to be activated in vitro or in vivo. Further, we found that upon T regulatory cell (Treg cell) specific inactivation of complex III, Treg cells survived, proliferated, and maintained stable Foxp3 expression but failed to function, resulting in a scurfy-like phenotype. Our findings identified mitochondria as necessary regulators of essential conventional and regulatory T cell functions. A central question based on our previous observations is how mitochondrial metabolism controls both conventional T cell and regulatory T cell function. We propose that mitochondrial metabolism is necessary for adaptive immune functions through the generation of ETC dependent reactive oxygen species (ROS) and production of TCA cycle metabolites to control transcription factors and chromatin/DNA modifications, respectively. Mitochondrial ETC complex I and III are the dominant sites of ROS generation. TCA cycle enzymes can elevate the production of succinate and L-2-hydroxygluatrate (L-2HG) to control DNA and histone methylation. Thus, we hypothesize that conventional CD8T cells require mitochondrial ROS for activation and memory differentiation; but that maintenance of memory CD8 T cells requires TCA cycle metabolites. Also, we postulate that mitochondrial TCA cycle metabolites control Treg suppressive function by controlling DNA methylation. To test this hypothesis, we propose the following aims: Specific Aim I: Determine whether complex I or III generated ROS are required for CD8 T cell activation, and memory formation while TCA cycle metabolites are essential for memory maintenance. Specific Aim II: Determine whether TCA cycle metabolites control Treg cell suppressive function. Together these aims will define the mechanisms by which mitochondria dictate T cell fate and function. 1

摘要 T细胞是适应性免疫应答和消退的主要介质。此前，我们发现，激活 T细胞也会增加线粒体耗氧率;在缺乏关键的 在电子传递链内复合物III的亚基，T细胞未能在体外或体内被激活。 此外，我们发现在复合物III的T调节细胞（Treg细胞）特异性失活后，Treg细胞存活， 增殖，并保持稳定的Foxp 3表达，但未能发挥功能，导致皮屑样表型。 我们的研究结果表明，线粒体是必需的常规和调节性T细胞 功能协调发展的基于我们先前的观察，一个中心问题是线粒体代谢如何控制 常规T细胞和调节性T细胞功能。我们认为线粒体代谢是 通过ETC依赖性活性氧的产生，是适应性免疫功能所必需的 (ROS)和TCA循环代谢产物的产生来控制转录因子和染色质/DNA 修改，分别。线粒体ETC复合物I和III是ROS产生的主要位点。 TCA循环酶可提高琥珀酸和L-2-羟基谷氨酸（L-2 HG）的产量，以控制DNA 和组蛋白甲基化。因此，我们假设传统的CD 8 T细胞需要线粒体ROS来维持其功能。 激活和记忆分化;但记忆CD 8 T细胞的维持需要TCA循环 代谢物。此外，我们假设线粒体TCA循环代谢物通过以下方式控制Treg抑制功能： 控制DNA甲基化。为了检验这一假设，我们提出了以下目标：具体目标一： 确定复合物I或III产生的ROS是否是CD 8 T细胞活化和记忆所需的 而TCA循环代谢物是维持记忆所必需的。具体目标二：确定 TCA循环代谢产物是否控制Treg细胞抑制功能。这些目标将共同定义 线粒体决定T细胞命运和功能的机制。 1