Metabolic control of regulatory T cell differentiation

调节性 T 细胞分化的代谢控制

• 批准号: 8303696
• 负责人: Hongbo Chi
• 金额: $ 21.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303696
• 关键词: Antigens; Applications Grants; Autoimmune Diseases; Autoimmune Process; Biological; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clonal Expansion; Complex; Data; Development; Disease; Effector Cell; Energy Metabolism; Exhibits; Exploratory/Developmental Grant; Future; G-Protein-Coupled Receptors; Generations; Goals; Graft Rejection; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunologic Receptors; Immunotherapy; Individual; Infection; Inflammatory; Intercept; Lead; Link; Lipids; Maintenance; Malignant Neoplasms; Mammals; Measures; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Modeling; Outcome; Pathway interactions; Peripheral; Play; Population; Process; Proteins; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Project Grants; Resources; Role; Series; Signal Transduction; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Thymus Gland; Tissues; Translating; Translations; Up-Regulation; cell type; cytokine; design; human FRAP1 protein; innovation; novel; prevent; response; sphingosine 1-phosphate; therapeutic target

DESCRIPTION (provided by applicant): When naive T cells encounter foreign antigen along with proper co-stimulation and cytokines, they undergo extensive clonal expansion and differentiate into specific lineages. In mammals, this type of proliferation is fairly unique to cels of the adaptive immune system and requires a considerable expenditure of energy and cellular resources. While research has often focused on the roles of cytokines, antigenic signals, and co- stimulation in guiding T cell responses, recent data indicate that, at a fundamental level, it s cellular metabolism that regulates T cell function and therefore influences the final outcome of the adaptive immune response. Indeed, a role for the metabolic pathways in T cell activation is beginning to be appreciated, but little is known about their involvement in the differentiation of regulatory T (Treg) cells, a central cell type in maintaining immune tolerance and inhibition of autoimmune and inflammatory diseases. We have found that S1P1, a G protein-coupled receptor (GPCR) for the bioactive lipid sphingosine 1-phosphate (S1P), inhibits differentiation of Treg cells. Moreover, S1P1 activates mTOR, a central regulator of protein translation, cellular metabolism and various other processes. Although activation of mTOR has been shown to restrain Treg differentiation, the mechanism involved remains unknown because of the pleiotropic functions of mTOR. We propose a novel concept that a low metabolic activity is actively regulated to allow the differentiation of Treg cells, and our long-term goal is to identif function and regulation of the metabolic machinery in T cell differentiation. In this exploratory/developmental grant application, we hypothesize that the S1P1-mTOR axis serves as a metabolic checkpoint to link cellular metabolism and negative control of Treg differentiation. We will test our hypothesis by establishing the signaling mechanisms of S1P1 and mTOR in Treg differentiation, and determining whether the metabolic machinery activated by S1P1 and mTOR controls Treg differentiation. These studies provide a series of tests and explorations of the new concept we propose, and hold the potential to greatly advance our understanding of the fundamental processes of cell metabolism and T cell differentiation. Moreover, given that S1P1 and mTOR are important therapeutic targets for transplant rejection and autoimmune and inflammatory diseases, our studies can be translated into innovative strategies to treat these immune-mediated diseases. PUBLIC HEALTH RELEVANCE: Regulatory T cells play a central role in the maintenance of immune tolerance to self tissues and in the down- modulation of the immune responses to infection and cancer. Abnormal functions of regulatory T cells can lead to autoimmune diseases as well as immunodeficiency. Therefore, a better understanding of the molecules and pathways involved in regulatory T cells is essential for future efforts to prevent and treat these immune- mediated diseases.

描述（由申请人提供）：当初始T细胞遇到外源抗原沿着适当的共刺激和细胞因子时，它们经历广泛的克隆扩增并分化成特定的谱系。在哺乳动物中，这种类型的增殖对于适应性免疫系统的细胞来说是相当独特的，并且需要消耗大量的能量和细胞资源。虽然研究通常集中在细胞因子，抗原信号和共刺激在引导T细胞应答中的作用，但最近的数据表明，在基本水平上，细胞代谢调节T细胞功能，因此影响适应性免疫应答的最终结果。事实上，代谢途径在T细胞活化中的作用开始受到重视，但对其参与调节性T（Treg）细胞的分化知之甚少，调节性T（Treg）细胞是维持免疫耐受和抑制自身免疫性和炎性疾病的中心细胞类型。我们已经发现，S1 P1，一个G蛋白偶联受体（GPCR）的生物活性脂质鞘氨醇1-磷酸（S1 P），抑制Treg细胞的分化。此外，S1 P1激活mTOR，这是蛋白质翻译、细胞代谢和各种其他过程的中心调节因子。尽管mTOR的激活已显示抑制Treg分化，但由于mTOR的多效性功能，所涉及的机制仍不清楚。我们提出了一个新的概念，即低代谢活性被主动调节以允许Treg细胞的分化，并且我们的长期目标是鉴定T细胞分化中代谢机制的功能和调节。在这个探索性/发展性资助申请中，我们假设S1 P1-mTOR轴作为一个代谢检查点，将细胞代谢和Treg分化的阴性控制联系起来。 我们将通过建立S1 P1和mTOR在Treg分化中的信号传导机制来验证我们的假设，并确定S1 P1和mTOR激活的代谢机制是否控制Treg分化。这些研究为我们提出的新概念提供了一系列测试和探索，并有可能极大地促进我们对细胞代谢和T细胞分化基本过程的理解。此外，鉴于S1 P1和mTOR是移植排斥、自身免疫和炎症性疾病的重要治疗靶点，我们的研究可以转化为治疗这些免疫介导疾病的创新策略。 公共卫生关系：调节性T细胞在维持对自身组织的免疫耐受性和下调对感染和癌症的免疫应答中起核心作用。调节性T细胞的功能异常可导致自身免疫性疾病以及免疫缺陷。因此，更好地了解调节性T细胞中涉及的分子和途径对于未来预防和治疗这些免疫介导的疾病的努力至关重要。