Bcl6 and transcription factors that program TFH differentiation and function

Bcl6 和转录因子编程 TFH 分化和功能

• 批准号: 10683269
• 负责人: Shane P Crotty
• 金额: $ 69.47万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683269
• 关键词: Address; Antibody Affinity; Antibody Response; Autoimmunity; B-Lymphocytes; BLR1 gene; Biology; CD 200; CD30L; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Chromatin; Civilization; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Disease; Future; GATA3 gene; Genes; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune response; Immunity; Immunobiology; Immunoglobulin Somatic Hypermutation; Interleukin-2; Knowledge; Laboratories; Light; Medical; Memory; Memory B-Lymphocyte; Modeling; Modernization; Molecular; Pathway interactions; Plasma Cells; Process; Provider; RUNX3 gene; Regulation; Repression; Scourge; Series; Structure of germinal center of lymph node; T cell differentiation; T-Lymphocyte; TNFSF11 gene; Technology; Testing; Vaccines; Viral Antibodies; Work; adaptive immunity; candidate identification; cost effective; effector T cell; experimental study; gene repression; genetic signature; improved; interleukin-21; mouse model; pathogen; programmed cell death protein 1; programs; synergism; tool; transcription factor; vaccine development; vaccinology

PROJECT SUMMARY / ABSTRACT Project 1 (Crotty) Helper T cell differentiation and function are important processes for many diseases. Vaccines are one of the most cost effective medical treatments in modern civilization. The vast majority of current human vaccines function by eliciting protective antibody responses. T cell help to B cells is a fundamental aspect of adaptive immunity to many pathogens. Follicular helper CD4 T cells (Tfh) are the specialized providers of help to B cells. Therefore, there is substantial potential for an improved understanding of Tfh cells to facilitate better anti- pathogen immune responses and vaccine-elicited humoral immunity. Work by our laboratory and others established that TFH cells depend on expression of the transcription factor Bcl6 and other transcription factors. Despite these advances, the pathways that control TFH differentiation and define TFH functions remain poorly understood. In Project 1, we will characterize, stratify, and interconnect TFs, chromatin regulators, and helper molecules that control TFH differentiation and function, leveraging our current tools and our team’s knowledge of related pathways in CD8 T cells (Projects 2 & 3). Aim 1. To understand the mechanisms of action of Bcl6 in TFH cell differentiation and function. Bcl6 is the lineage defining transcription factor of TFH cells. How Bcl6 accomplishes control of TFH differentiation and function remains unclear, because of the complexity of the biology. Based on preliminary data, our operating model is that Bcl6 controls TFH differentiation by repressor-of- repressor mechanisms. Putative mechanisms will be comprehensively tested. Aim 2. Aim 1 has identified and will identify key Bcl6-r TFs. In Aim 2 we explore the biology of these TFs and the putative mechanisms by which these TFs control TFH. Aim 3. TFH help to B cells is a multifaceted process for which much is still unknown regarding the molecules involved. This is in part because it is a complex set of functions, and in part because of previous technological limitations. It is likely that elucidating the immunobiology underlying the differentiation of Tfh cells and the process of generating protective antiviral antibody responses will reveal vaccinology principles that can be applied to future vaccine development against infectious scourges.

项目总结/摘要 项目1（Crotty） 辅助性T细胞的分化和功能是许多疾病的重要过程。疫苗是一种 最具成本效益的医疗方法。目前绝大多数的人类疫苗 通过引发保护性抗体反应发挥作用。T细胞对B细胞的帮助是适应性免疫的一个基本方面。 对许多病原体的免疫力。滤泡辅助性CD 4 T细胞（Tfh）是专门帮助B细胞的提供者。 因此，有很大的潜力，提高对Tfh细胞的理解，以促进更好的抗肿瘤治疗。 病原体免疫应答和疫苗引起的体液免疫。我们实验室和其他机构的工作 建立了TFH细胞依赖于转录因子Bcl 6和其他转录因子的表达。 尽管有这些进展，控制TFH分化和定义TFH功能的途径仍然很差 明白在项目1中，我们将表征，分层，并互连TF，染色质调节剂和辅助因子。 控制TFH分化和功能的分子，利用我们目前的工具和我们团队的知识， CD 8 T细胞相关通路（项目2和3）。目标1.了解Bcl 6在TFH中的作用机制 细胞分化和功能。Bcl 6是TFH细胞的谱系定义转录因子。如何Bcl 6 由于TFH分化和功能的复杂性， 生物学基于初步的数据，我们的操作模型是Bcl 6通过抑制因子-β 1来控制TFH分化。 阻遏机制将对假定的机制进行全面测试。目标2.目标1已确定， 将鉴定关键的Bcl 6-r TF。在目标2中，我们探索了这些TF的生物学和推测的机制， 这些TF控制TFH。目标3。TFH对B细胞的帮助是一个多方面的过程，其中许多仍然是未知的 关于所涉及的分子这部分是因为它是一组复杂的功能，部分是因为 以前的技术限制。很可能阐明免疫生物学的分化， TFH细胞和产生保护性抗病毒抗体应答的过程将揭示疫苗学原理 可以应用于未来针对传染性疾病的疫苗开发。