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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：
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

摘要