Molecular characterization of the role for T-bet and Bcl-6 in immune cell metabolism and differentiation

T-bet 和 Bcl-6 在免疫细胞代谢和分化中作用的分子表征

基本信息

  • 批准号:
    9241941
  • 负责人:
  • 金额:
    $ 36.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-06-01 至 2021-02-28
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Lineage-specifying transcription factors coordinate a diverse array of cellular processes for the appropriate differentiation of the cell. In CD4+ T cell, the T-box transcription factor T-bet is required for the development of T helper type 1 (Th1) cells, whereas the BTB-zinc finger (ZF) factor Bcl-6 is required for T follicular helper (Tfh) cell development. Importantly, the balance between these two lineage-specifying factors also influences the effector versus memory cell transition in CD4+ and CD8+ T cells. To date, our understanding of the gene expression programs that the balance between T-bet and Bcl-6 regulate to control the effector versus memory transition have been incomplete. Recent research in the field has highlighted the importance of metabolic states in the differentiation and functional potential of immune cells. In T cells, a high rate of glycolysis is needed for effector ell differentiation whereas the glycolysis pathway is dampened in favor of the fatty acid oxidation (FAO) pathway in memory cells. Notably, artificially inhibiting the glycolytic pathway in CD8+ T cells can effectively promote memory cell differentiation. Thus, the regulation of cellular metabolism is important for the effector versus memory cell transition and targeting the metabolic state of T cells represents a novel way to control this decision in autoimmune states and vaccine strategies. In new research from my laboratory, we have shown for that the balance between T-bet and Bcl-6 is important for the IL-2-sensitive regulation of the glycolysis gene expression program. Our new data suggest that at least in part, the close connection between cellular metabolism and differentiation states is because these processes are mechanistically regulated by a similar complement of lineage-specifying transcription factors. In this proposal we will define how different environmental conditions in vitro and microenvironments in vivo influence the expression of the metabolic gene program and metabolite accumulation in effector versus memory T cells, and determine the role for the balance between T-bet and Bcl-6 in these processes. We will also define the role for metabolites in regulating specialization programs in T cells and whether T-bet and Bcl-6 contribute to targeting their activities. This is a critical new direction of research to pursue because it has the potential to provide new therapeutic opportunities to redirect immune cell differentiation using clinically approved metabolic inhibitors. In the case of memory cell development, this will aid in vaccination strategies for viruses such as HIV and HCV where robust long-term memory responses have not yet been achieved. For autoimmune conditions, this has the potential to dampen the aberrant activities that cause tissue specific pathologies. Therefore, the basic knowledge gained in these studies will increase our future potential to logically target metabolic pathways to enhance immunity and treat conditions caused by pathogenic immune responses.
 描述(申请人提供):谱系特定的转录因子协调一系列不同的细胞过程,以实现细胞的适当分化。在CD4+T细胞中,T辅助1型(Th1)细胞的发育需要T盒转录因子T-bet,而T滤泡辅助(Tfh)细胞则需要BTB-锌指(ZF)因子Bcl-6 发展。重要的是,这两个谱系特定因子之间的平衡也影响了CD4+和CD8+T细胞中效应器与记忆细胞的转换。到目前为止,我们对T-bet和Bcl-6之间的平衡调节以控制效应器和记忆转换的基因表达程序的理解还不完整。最近该领域的研究强调了代谢状态在分化和 免疫细胞的功能潜力。在T细胞中,效应细胞的分化需要高水平的糖酵解,而在记忆细胞中,糖酵解途径被抑制,有利于脂肪酸氧化(FAO)途径。值得注意的是,人工抑制CD8+T细胞的糖酵解途径可以有效地促进记忆细胞的分化。因此,细胞代谢的调节对于效应器与记忆细胞的转换是重要的,靶向T细胞的代谢状态是在自身免疫状态和疫苗策略中控制这一决定的一种新方法。在我的实验室的新研究中,我们已经证明T-bet和Bcl-6之间的平衡对于糖酵解基因表达程序中IL-2敏感的调节是重要的。我们的新数据表明,至少在一定程度上,细胞新陈代谢和分化状态之间的密切联系是因为这些过程受到类似的谱系特定转录因子的机械调节。在这个方案中,我们将定义不同的体外环境条件和体内微环境如何影响效应T细胞和记忆T细胞代谢基因程序的表达和代谢物的积累,并确定T-bet和Bcl-6之间的平衡在这些过程中的作用。我们还将确定代谢物在调节T细胞特化程序中的作用,以及T-bet和Bcl-6是否有助于靶向它们的活动。这是一个关键的新研究方向,因为它有可能提供新的治疗机会,使用临床批准的代谢抑制剂重新引导免疫细胞分化。在记忆细胞发育的情况下,这将有助于针对艾滋病毒和丙型肝炎病毒等病毒的疫苗接种策略,这些病毒尚未实现强大的长期记忆反应。对于自身免疫条件,这有可能抑制导致组织特异性病理的异常活动。因此,在这些研究中获得的基本知识将增加我们未来在逻辑上针对代谢途径以增强免疫力和治疗由病原性免疫反应引起的疾病的潜力。

项目成果

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Amy Susan Weinmann其他文献

Amy Susan Weinmann的其他文献

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{{ truncateString('Amy Susan Weinmann', 18)}}的其他基金

Genome organization, evolutionary structural variation, and gene regulation in immunity
免疫中的基因组组织、进化结构变异和基因调控
  • 批准号:
    10662147
  • 财政年份:
    2023
  • 资助金额:
    $ 36.75万
  • 项目类别:
The Molecular Mechanisms of Immune Cell Development and Function
免疫细胞发育和功能的分子机制
  • 批准号:
    10751580
  • 财政年份:
    2023
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular characterization of the role for metabolites in immune cell differentiation
代谢物在免疫细胞分化中作用的分子表征
  • 批准号:
    10455211
  • 财政年份:
    2021
  • 资助金额:
    $ 36.75万
  • 项目类别:
Tet1 activity and function in helper T cells
辅助 T 细胞中的 Tet1 活性和功能
  • 批准号:
    8897261
  • 财政年份:
    2014
  • 资助金额:
    $ 36.75万
  • 项目类别:
Tet1 activity and function in helper T cells
辅助 T 细胞中的 Tet1 活性和功能
  • 批准号:
    8754547
  • 财政年份:
    2014
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
  • 批准号:
    6811196
  • 财政年份:
    2004
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
  • 批准号:
    8414841
  • 财政年份:
    2004
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
  • 批准号:
    8212463
  • 财政年份:
    2004
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
  • 批准号:
    6892078
  • 财政年份:
    2004
  • 资助金额:
    $ 36.75万
  • 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
  • 批准号:
    7230470
  • 财政年份:
    2004
  • 资助金额:
    $ 36.75万
  • 项目类别:
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