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Mitochondria regulate adaptive immunity

线粒体调节适应性免疫

基本信息

批准号：
10242090
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
项目类别：
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/10242090
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

项目摘要

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

抽象的 T 细胞是适应性免疫反应和解决的主要介质。之前我们发现激活 T 细胞也会增加线粒体耗氧率；并且在没有关键的情况下由于电子传递链内复合物III亚基的存在，T细胞在体外或体内均未能被激活。此外，我们发现，当复合物 III 特异性失活 T 调节细胞（Treg 细胞）时，Treg 细胞得以存活，增殖并保持稳定的 Foxp3 表达，但无法发挥作用，导致出现头屑样表型。我们的研究结果确定线粒体是必需的常规 T 细胞和调节性 T 细胞的必要调节者功能。根据我们之前的观察，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 细胞都具有功能。我们认为线粒体代谢是通过产生 ETC 依赖性活性氧来实现适应性免疫功能所必需的 (ROS) 和 TCA 循环代谢物的产生来控制转录因子和染色质/DNA 分别进行修改。线粒体 ETC 复合体 I 和 III 是 ROS 生成的主要位点。 TCA 循环酶可以提高琥珀酸和 L-2-羟基戊二酸 (L-2HG) 的产量来控制 DNA 和组蛋白甲基化。因此，我们假设传统的 CD8T 细胞需要线粒体 ROS 激活和记忆分化；但记忆 CD8 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，我们提出以下目标：具体目标 I：确定 CD8 T 细胞激活和记忆是否需要复合物 I 或 III 生成的 ROS 而 TCA 循环代谢物对于记忆维持至关重要。具体目标 II：确定 TCA循环代谢物是否控制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