Metabolic control of regulatory T cell differentiation

调节性 T 细胞分化的代谢控制

基本信息

  • 批准号:
    8416361
  • 负责人:
  • 金额:
    $ 26.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
描述(由申请人提供):当幼稚T细胞遇到外来抗原以及适当的共刺激和细胞因子时,它们会进行广泛的克隆扩增并分化成特定的谱系。在哺乳动物中,这种类型的增殖是适应性免疫系统细胞所特有的,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指导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,从而影响适应性免疫应答的最终结果。事实上,代谢途径在T细胞活化中的作用已开始得到重视,但它们在调节性T细胞(Treg)分化中的作用知之甚少,Treg细胞是维持免疫耐受和抑制自身免疫和炎症性疾病的中心细胞类型。我们发现S1P1,一个生物活性脂质鞘氨醇1-磷酸(S1P)的G蛋白偶联受体(GPCR),抑制Treg细胞的分化。此外,S1P1激活mTOR, mTOR是蛋白质翻译、细胞代谢和各种其他过程的中心调节因子。虽然mTOR的激活已被证明可以抑制Treg分化,但由于mTOR的多效性,其机制尚不清楚。我们提出了一个新的概念,即低代谢活性被积极调节以允许Treg细胞分化,我们的长期目标是确定T细胞分化中代谢机制的功能和调节。在这项探索性/发展性拨款申请中,我们假设S1P1-mTOR轴作为代谢检查点,将细胞代谢和Treg分化的负控制联系起来。

项目成果

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Hongbo Chi其他文献

Hongbo Chi的其他文献

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{{ truncateString('Hongbo Chi', 18)}}的其他基金

Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology
通过系统免疫学对高危 3 组髓母细胞瘤进行免疫治疗
  • 批准号:
    10714138
  • 财政年份:
    2023
  • 资助金额:
    $ 26.25万
  • 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
  • 批准号:
    10442703
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
  • 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
  • 批准号:
    10299800
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
  • 项目类别:
2020 Immunometabolism in Health and Disease GRC
2020 健康与疾病中的免疫代谢 GRC
  • 批准号:
    9912281
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
  • 项目类别:
Integrating systems immunology with immunometabolism and cancer immunity
将系统免疫学与免疫代谢和癌症免疫相结合
  • 批准号:
    10657475
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
  • 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
  • 批准号:
    10020901
  • 财政年份:
    2019
  • 资助金额:
    $ 26.25万
  • 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
  • 批准号:
    10687027
  • 财政年份:
    2019
  • 资助金额:
    $ 26.25万
  • 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
  • 批准号:
    10466976
  • 财政年份:
    2019
  • 资助金额:
    $ 26.25万
  • 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
  • 批准号:
    10231172
  • 财政年份:
    2019
  • 资助金额:
    $ 26.25万
  • 项目类别:
Bidirectional metabolic signaling in follicular helper T cell differentiation
滤泡辅助 T 细胞分化中的双向代谢信号
  • 批准号:
    9917280
  • 财政年份:
    2019
  • 资助金额:
    $ 26.25万
  • 项目类别:
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