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: 10024587
• 负责人: Shane P Crotty
• 金额: $ 56.21万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024587
• 关键词: Address; Antibodies; 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; Scourge; Series; Structure of germinal center of lymph node; T cell differentiation; T-Lymphocyte; TNFSF11 gene; Testing; Vaccines; Viral Antibodies; Work; adaptive immunity; base; cost effective; effector T cell; experimental study; genetic signature; improved; interleukin-21; mouse model; pathogen; programmed cell death protein 1; programs; synergism; tool; transcription factor; vaccine development; vaccinology; vpr Genes

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.

项目概要/摘要 项目 1（克罗蒂） 辅助 T 细胞的分化和功能是许多疾病的重要过程。疫苗是其中之一 现代文明中最具成本效益的医疗方法。目前绝大多数人类疫苗 通过引发保护性抗体反应来发挥作用。 T 细胞对 B 细胞的帮助是适应性的一个基本方面 对许多病原体具有免疫力。滤泡辅助 CD4 T 细胞 (Tfh) 是 B 细胞的专门帮助提供者。 因此，增进对 Tfh 细胞的了解以促进更好的抗-Tfh 细胞具有巨大的潜力。 病原体免疫反应和疫苗引起的体液免疫。我们实验室和其他实验室的工作 确定 TFH 细胞依赖于转录因子 Bcl6 和其他转录因子的表达。 尽管取得了这些进展，但控制 TFH 分化和定义 TFH 功能的途径仍然很差 明白了。在项目 1 中，我们将表征、分层和互连 TF、染色质调节因子和辅助因子 控制 TFH 分化和功能的分子，利用我们现有的工具和我们团队的知识 CD8 T 细胞中的相关途径（项目 2 和 3）。目标 1. 了解 Bcl6 在 TFH 中的作用机制 细胞分化和功能。 Bcl6 是 TFH 细胞谱系定义转录因子。 Bcl6如何 由于 TFH 的复杂性，其如何实现对 TFH 分化和功能的控制仍不清楚。 生物学。根据初步数据，我们的操作模型是 Bcl6 通过阻遏物控制 TFH 分化 抑制机制。假定的机制将受到全面测试。目标 2. 目标 1 已确定并 将识别关键的 Bcl6-r TF。在目标 2 中，我们探讨了这些转录因子的生物学特性以及假定的机制 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，其中还有很多未知之处 关于所涉及的分子。部分原因是它是一组复杂的函数，部分原因是 以前的技术限制。很可能阐明了分化背后的免疫生物学 Tfh细胞和产生保护性抗病毒抗体反应的过程将揭示疫苗学原理 这可以应用于未来针对传染病的疫苗开发。