Innate T cell metabolism and immune diseases

 描述(申请人提供)：NKT细胞是先天的类T细胞，倾向于存在于非淋巴组织中，并具有慢性激活或记忆细胞的标记。当被激活时，NKT细胞表现出快速和更强大的效应功能，如细胞因子释放或细胞毒作用。它们被认为是迅速出现的先天免疫和较缓慢出现的获得性免疫之间的桥梁。胸腺来源的NKT细胞在外围经历了进一步的分化和功能特化，促使它们混合到非淋巴组织，如肝脏和脂肪组织。因此，NKT细胞是一个异质性群体，在非淋巴组织中具有高度的表型和功能特化。最近在不同临床和实验环境中的研究表明，虽然NKT细胞更多地是致病的，但它们也是调节的。NKT细胞在肝脏和脂肪组织中含量丰富，这两个器官在间质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被证明在决定T细胞激活和效应器功能的结果中起着至关重要的作用。不同的T细胞亚群采用特定的新陈代谢计划来支持他们的需求。当T细胞激活时，线粒体产生活性氧物种(ROS)，这是T细胞激活所必需的。大量证据表明，ROS是先天和获得性免疫细胞中必不可少的第二信使。然而，免疫细胞内ROS水平的增加会导致炎症反应的过度激活，从而导致组织损伤和病理。尽管人们对CD4和CD8T细胞的代谢需求和调节进行了大量的研究，但对NKT细胞的代谢调节知之甚少。我们的初步研究表明，新鲜分离的肝脏NKT细胞比CD4T细胞具有更高的ROS，而驻留在内脏脂肪组织中的NKT细胞表现出与CD4T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。根据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崩溃会导致炎症和组织损伤，从而导致自身免疫性肝炎和肥胖。为了验证这一假说，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性免疫疾病：肝脏炎症和肥胖。鉴于NKT细胞在免疫疾病中的重要作用，研究NKT细胞对细胞代谢、氧化应激和免疫疾病的调控具有重要的创新性和现实意义。

 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.