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

• 批准号: 9241941
• 负责人: Amy Susan Weinmann
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9241941
• 关键词: Autoimmune Process; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular Metabolic Process; Clinical; Complement; Complex; Cues; DNA Modification Process; Data; Development; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Failure; Feedback; Funding; Future; Gene Expression; Generations; Genes; Genetic Transcription; Genome; Genomics; Glycolysis; Glycolysis Pathway; Grant; HIV/HCV; Helper-Inducer T-Lymphocyte; Hematopoietic Neoplasms; Immune; Immune System Diseases; Immune response; Immune system; Immunity; In Vitro; Infection Control; Intake; Interleukin-2; Knowledge; Laboratories; Link; Memory; Metabolic; Metabolic Pathway; Metabolism; Modification; Molecular; Nutrient; Pathogenicity; Pathologic; Pathology; Pathway interactions; Play; Process; Production; Proliferating; Recruitment Activity; Regulation; Research; Research Support; Role; Signal Transduction; Source; Specific qualifier value; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Th1 Cells; Tissues; Transcription Factor Oncogene; Translating; Vaccines; Virus; Vitamins; Zinc Fingers; cancer cell; cancer therapy; cell growth regulation; embryonic stem cell; epigenome; experimental study; fatty acid oxidation; histone modification; in vivo; inhibitor/antagonist; long term memory; novel; novel therapeutics; programs; public health relevance; response; sugar; transcription factor; vaccination strategy

 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。