Innate T cell metabolism and immune diseases

先天性T细胞代谢与免疫疾病

• 批准号: 9193058
• 负责人: Cheong-Hee Chang
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193058
• 关键词: Adipose tissue; Adopted; Alpha Cell; Antioxidants; Apoptotic; Autoimmune Diseases; Autoimmune Hepatitis; Behavior; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cells; Cellular Metabolic Process; Cellular Stress; Characteristics; Chronic; Clinical; Communicable Diseases; Cues; Data; Development; Disease; Disease model; Exhibits; Experimental Models; Generations; Genetic; Glucose Transporter; Growth; Health system; Hepatic; Hepatitis; Hepatocyte; Human; Hydrogen Peroxide; Immune; Immune System Diseases; Immunologic Factors; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Liver; Mediating; Memory; Metabolic; Metabolic Diseases; Metabolism; Mission; Mitochondria; Natural Immunity; Nature; Nutrient; Obesity; Organ; Outcome; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Pharmacology; Phenotype; Play; Population Heterogeneity; Public Health; Publishing; Reactive Oxygen Species; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Source; Spleen; Stress; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Time; Tissues; United States National Institutes of Health; Visceral; ZNF145 gene; adaptive immunity; base; cytokine; cytotoxicity; design; in vivo; innovation; insight; liver inflammation; macromolecule; metabolic profile; prevent; programs; public health relevance; response; therapy design; transcription factor

 DESCRIPTION (provided by applicant): NKT cells are innate-like T cells and tend to reside in non-lymphoid tissues and to have markers of chronically activated or memory cells. When activated, NKT cells exhibit a fast and more robust effector function such as cytokine release or cytotoxicity. They are thought to serve as a bridge between the rapidly occurring innate immunity and the more slowly occurring adaptive immunity. Thymus-derived NKT cells undergo further differentiation and functional specialization in the periphery that promotes their migratio into non-lymphoid tissues such as the liver and adipose tissue. Therefore, NKT cells are a heterogeneous population with a high degree of phenotypic and functional specialization in non-lymphoid tissues. The recent studies in different clinical and experimental settings showed that while NKT cells are more often pathogenic, they are also regulatory. NKT cells are abundant in the liver and adipose tissue, two organs that play a critical role in the development of metainflammation. Recently, the signaling pathways that control cellular metabolism have been shown to have a crucial role in dictating the outcome of T cell activation and effector function. Distinct T cell subsets adopt metabolic programs specific to support their needs. Upon T cell activation, reactive oxygen species (ROS) is produced by mitochondria, which is required for T-cell activation. Substantial evidence has revealed that ROS are essential second messengers in innate and adaptive immune cells. Yet increased levels of ROS within immune cells can result in hyperactivation of inflammatory responses, resulting in tissue damage and pathology. Although much effort has put forth to understand metabolic needs and regulation of CD4 and CD8 T cells, little is known about the metabolic regulation of NKT cells. Our preliminary studies showed that freshly isolated NKT cells from the liver have high ROS than CD4 T cells, whereas NKT cells resident in visceral adipose tissue show low ROS similar to CD4 T cells. Interestingly, NKT cells in these two tissues have an opposing function. Based on the published studies and our preliminary data, we hypothesize that the breakdown of tolerance of cell metabolism of NKT cells leads to inflammation and tissue damage resulting in autoimmune hepatitis and obesity. To test the hypothesis, we will investigate the metabolic regulation in NKT cells and how cell metabolism of NKT cells regulates two distinct metabolic immune diseases, liver inflammation and obesity. Given the importance of NKT cells as a critical factor for immune diseases, studying the regulation of cell metabolism, oxidative stress and immune diseases mediated by NKT cells is highly innovative and significant.

 描述（由申请人提供）：NKT细胞是先天性T细胞样细胞，倾向于驻留在非淋巴组织中，并具有慢性激活或记忆细胞的标志物。当被激活时，NKT细胞表现出快速和更强大的效应子功能，如细胞因子释放或细胞毒性。它们被认为是快速发生的先天免疫和更缓慢发生的适应性免疫之间的桥梁。胸腺来源的NKT细胞在外周中经历进一步分化和功能特化，这促进它们迁移到非淋巴组织如肝脏和脂肪组织中。因此，NKT细胞是在非淋巴组织中具有高度表型和功能特化的异质群体。最近在不同临床和实验环境中的研究表明，虽然NKT细胞更经常是致病性的，但它们也是调节性的。NKT细胞在肝脏和脂肪组织中大量存在，这两个器官在炎症的发展中起着关键作用。最近，控制细胞代谢的信号通路已被证明在决定T细胞活化和效应器功能的结果中具有至关重要的作用。不同的T细胞亚群采用特定的代谢程序来支持其需求。在T细胞活化时，线粒体产生活性氧（ROS），这是T细胞活化所需的。大量证据表明，ROS是先天性和适应性免疫细胞中必不可少的第二信使。然而，免疫细胞内ROS水平的增加可导致炎症反应的过度活化，从而导致组织损伤和病理学。尽管已经做出了很多努力来了解CD4和CD8 T细胞的代谢需求和调节，但对NKT细胞的代谢调节知之甚少。我们的初步研究表明，从肝脏新鲜分离的NKT细胞具有比CD4 T细胞高的ROS，而内脏脂肪组织中的NKT细胞显示出与CD4 T细胞相似的低ROS。有趣的是，这两种组织中的NKT细胞具有相反的功能。基于已发表的研究和我们的初步数据，我们假设NKT细胞的细胞代谢耐受性的破坏导致炎症和组织损伤，从而导致自身免疫性肝炎和肥胖。为了验证这一假设，我们将研究NKT细胞的代谢调节以及NKT细胞的细胞代谢如何调节两种不同的代谢免疫疾病，肝脏炎症和肥胖。鉴于NKT细胞作为免疫疾病的关键因素的重要性，研究NKT细胞介导的细胞代谢、氧化应激和免疫疾病的调节具有高度的创新性和意义。