Regulation of metabolic pathways in NKT cells

NKT 细胞代谢途径的调节

• 批准号: 10212213
• 负责人: Cheong-Hee Chang
• 金额: $ 54.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212213
• 关键词: Address; Adipose tissue; Adopted; Area; Autoimmune Diseases; Biochemical Pathway; Bioenergetics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Carbon; Cell Cycle Progression; Cell Respiration; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Cytotoxic T-Lymphocytes; Data; Development; Diabetes Mellitus; Ectopic Expression; Environment; Enzymes; Equilibrium; Exhibits; Experimental Models; Gene Expression; Generations; Glucose; Glutamates; Glutamine; Glutathione; Glycolysis; Growth; Health system; Human; Human Characteristics; Immune System Diseases; Immune response; Infection; Inflammatory; Interferons; Knowledge; Liver; Malignant Neoplasms; Measures; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Outcome; Outcome Study; Oxidative Phosphorylation; Pathogenesis; Pentosephosphate Pathway; Phenotype; Play; Population Heterogeneity; Production; Proliferating; Public Health; Publishing; Reactive Oxygen Species; Regulation; Research; Rest; Role; Signal Pathway; Signal Transduction; Site; Source; Starvation; T cell differentiation; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Thymus Gland; Time; Tissues; United States National Institutes of Health; ZNF145 gene; aerobic glycolysis; arm; base; cancer cell; cytokine; cytotoxicity; glucose metabolism; glucose uptake; innovation; insight; macromolecule; metabolomics; programs; response; therapy design; virtual

ABSTRACT In conventional T cells, signaling pathways that control cellular metabolism have a crucial role in dictating the outcome of T cell activation and their effector function. Resting CD4 and CD8 T cells use predominantly oxidative metabolism but stimulation leads them to sharply increase glucose metabolism and adopt aerobic glycolysis as a primary metabolic program. However, little is known about metabolic regulation and its role for cellular functions of Natural Killer T (NKT) cells although recent studies indicate an important role of metabolism in NKT cell differentiation. NKT cells are a heterogeneous population that shows a high degree of phenotypic and functional specialization. When activated, unlike conventional T cells, NKT cells exhibit a fast and robust effector function such as cytokine release or cytotoxicity. NKT cells can exert either an inflammatory or a regulatory function depending on the tissue type such as liver or adipose tissue, respectively, that are a site of metainflammation. Thus, the metabolic regulation in NKT cells likely plays an important role in immune diseases. To understand how NKT cells regulate their metabolism to mediate an appropriate immune response under a different environment, we measured parameters that associate with the metabolic capacity and compared them with that of CD4 T cells. Our study revealed that NKT cells are very different from CD4 T cells in many ways. NKT cells rely more on oxidative phosphorylation for their survival and repurposed Glc carbon is used for optimal cytokine expression. In addition, NKT cells rely on glutamine (Gln) metabolism for proliferation but not to express IFN-. Gln starved NKT cells seem to be inefficient to switch to glucose (Glc) metabolism, which is similar to Gln-addicted cancer cells. Metabolomic data revealed that NKT cells have elevated glutamine metabolites prior to stimulation further supporting an essential role of Gln metabolism. mTORC and AMPK is known to increase and decrease Gln metabolism, respectively. In line with this, NKT cells are sensitive to mTORC inhibition but AMPK deficiency results in hyperproliferation and increased cytokine expression. Based on our data, we hypothesize that the proper regulation of Gln metabolism is critical for NKT cells’ survival and function, which is controlled by the balance between mTORC and AMPK activity. To test the hypothesis, we propose two specific aims. Aim 1 will investigate the mechanisms by which Gln controls NKT cell proliferation and function, and Aim 2 will focus on the mTORC-AMPK axis to discern the regulation of Gln metabolism in NKT cells. Metabolic status and regulation in NKT cells is virtually unexplored and, therefore, investigating the regulation of the metabolic networks in NKT cells is highly innovative. Undoubtedly, the proposed studies are significant given the fact that these studies will address a poorly understood area, and the results will establish specific and selective metabolic demands of NKT cells.

摘要 在传统的T细胞中，控制细胞代谢的信号传导通路在决定T细胞的功能中起着至关重要的作用。 T细胞活化及其效应子功能的结果。静息的CD4和CD8 T细胞主要使用 氧化代谢，但刺激导致他们急剧增加葡萄糖代谢，并采取有氧 糖酵解作为主要的代谢程序。然而，人们对代谢调节及其在代谢中的作用知之甚少。 自然杀伤T（NKT）细胞的细胞功能，虽然最近的研究表明， NKT细胞分化中的代谢。NKT细胞是一种异质性群体，其显示出高度的细胞分化。 表型和功能特化。当被激活时，与传统的T细胞不同，NKT细胞表现出快速的免疫反应。 和稳健的效应子功能如细胞因子释放或细胞毒性。NKT细胞可以产生炎症反应， 或调节功能，这取决于组织类型，例如分别是肝或脂肪组织， 后炎症部位。因此，NKT细胞的代谢调节可能在免疫调节中起重要作用。 疾病了解NKT细胞如何调节其代谢以介导适当的免疫反应 在不同的环境下，我们测量了与代谢能力相关的参数， 并与CD4 T细胞进行了比较。我们的研究表明，NKT细胞与CD4 T细胞非常不同， 在很多方面。NKT细胞更多地依赖于氧化磷酸化来存活， 用于最佳细胞因子表达。此外，NKT细胞依赖于谷氨酰胺（Gln）代谢进行增殖 但不表达IFN-γ。Gln饥饿的NKT细胞似乎不能有效地转换为葡萄糖（Glc）代谢， 类似于谷氨酰胺成瘾的癌细胞代谢组学数据显示，NKT细胞具有升高的 在刺激之前，谷氨酰胺代谢物的增加进一步支持Gln代谢的重要作用。mTORC和 已知AMPK分别增加和减少Gln代谢。与此同时，NKT细胞 对mTORC抑制敏感，但AMPK缺乏导致过度增殖和细胞因子增加 表情基于我们的数据，我们假设谷氨酰胺代谢的适当调节对NKT至关重要 细胞的存活和功能，这是由mTORC和AMPK活性之间的平衡控制。测试 假设，我们提出了两个具体目标。目标1将研究Gln控制NKT的机制 细胞增殖和功能，Aim 2将集中在mTORC-AMPK轴上，以识别Gln的调节 NKT细胞的代谢。NKT细胞中的代谢状态和调节几乎未被探索，因此， 研究NKT细胞中代谢网络的调节是高度创新的。无疑 鉴于这些研究将解决人们知之甚少的领域，因此拟议的研究意义重大，并且 结果将建立NKT细胞的特异性和选择性代谢需求。