Mitochondria regulate adaptive immunity

线粒体调节适应性免疫

基本信息

批准号：
10021395
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/10021395
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分辨率的主要介体。以前，我们发现已激活 T细胞还增加了线粒体氧的消耗率；在没有批判的情况下电子传输链中复合物III的亚基，T细胞在体外或体内未能激活。此外，我们发现，在调节细胞（Treg细胞）对复合物III的特异性失活后，Treg细胞幸存下来，增殖并保持稳定的FOXP3表达，但无法发挥作用，从而导致了类似于表型的表型。我们的发现将线粒体确定为必要的常规和调节性T细胞的必要调节剂功能。基于我们以前观察的一个中心问题是线粒体代谢如何控制常规的T细胞和调节性T细胞功能。我们建议线粒体代谢是通过产生依赖的活性氧的自适应免疫功能所必需的（ROS）和TCA循环代谢产物的产生以控制转录因子和染色质/DNA 分别进行修改。线粒体等复合物I和III是ROS产生的主要位点。 TCA循环酶可以提高琥珀酸酯和L-2-羟基氟酸酯（L-2HG）的产生，以控制DNA 和组蛋白甲基化。因此，我们假设常规CD8T细胞需要线粒体ROS的激活和记忆分化；但是记忆CD8 T细胞的维护需要TCA循环代谢物。另外，我们假设线粒体TCA循环代谢产物控制Treg抑制功能控制DNA甲基化。为了检验这一假设，我们提出以下目的：特定目的I：确定CD8 T细胞激活是否需要复杂的I或III生成的ROS，并记忆 TCA周期代谢物对于记忆维持至关重要。特定目标II：确定 TCA循环代谢物是否控制Treg细胞抑制功能。这些目标共同定义线粒体决定T细胞命运和功能的机制。 1