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

 描述（由申请人提供）：谱系特异性转录因子协调多种细胞过程以实现细胞的适当分化。在CD 4 + T细胞中，T-box转录因子T-bet是Th 1细胞发育所必需的，而BTB-锌指（ZF）因子Bcl-6是Tfh细胞发育所必需的。 发展重要的是，这两种谱系特异性因子之间的平衡也影响CD 4+和CD 8 + T细胞中效应细胞与记忆细胞的转换。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与记忆转换的基因表达程序的理解还不完整。该领域的最新研究强调了代谢状态在分化和分化中的重要性。 免疫细胞的功能潜力。在T细胞中，效应细胞分化需要高速率的糖酵解，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CD 8 + T细胞中的糖酵解途径可以有效地促进记忆细胞分化。因此，细胞代谢的调节对于效应细胞与记忆细胞的转换是重要的，并且靶向T细胞的代谢状态代表了在自身免疫状态和疫苗策略中控制该决定的新方法。在我实验室的新研究中，我们已经表明T-bet和Bcl-6之间的平衡对于糖酵解基因表达程序的IL-2敏感性调节是重要的。我们的新数据表明，至少在一定程度上，细胞代谢和分化状态之间的密切联系是因为这些过程是由一个类似的谱系特异性转录因子的补充机制。在这个提议中，我们将定义不同的环境条件在体外和微环境在体内如何影响代谢基因程序的表达和代谢物在效应与记忆T细胞中的积累，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细胞专业化程序中的作用，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定向免疫细胞分化。在记忆细胞发育的情况下，这将有助于艾滋病毒和HCV等病毒的疫苗接种策略，其中尚未实现强大的长期记忆反应。对于自身免疫性疾病，这有可能抑制导致组织特异性病理的异常活动。因此，这些研究中获得的基础知识将增加我们未来合理靶向代谢途径的潜力，以增强免疫力并治疗病原性免疫反应引起的疾病。

 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.