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: 10224892
• 负责人: Shane P Crotty
• 金额: $ 30.24万
• 依托单位: SCRIPPS 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 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224892
• 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.

项目摘要/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 现代文明中最具成本效益的医疗方法。目前绝大多数的人类疫苗 通过激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的一个基本方面 对许多病原体免疫。滤泡辅助性T细胞(TFH)是为B细胞提供帮助的专门化细胞。 因此，对TFH细胞的了解有很大的潜力，以促进更好的抗 病原体免疫反应和疫苗诱导的体液免疫。我们的实验室和其他机构的工作 证实TFH细胞依赖转录因子Bcl6和其他转录因子的表达。 尽管有这些进展，但控制TFH分化和确定TFH功能的途径仍然很差 明白了。在项目1中，我们将对TF、染色质调节器和助手进行表征、分层和互连 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对 CD8T细胞中的相关通路(方案2和3)。目的1.了解Bcl6在TFH中的作用机制 细胞分化和功能。Bcl6是TFH细胞的家族决定转录因子。Bcl6如何 完成对TFH分化的控制，由于TFH的复杂性，其功能尚不清楚 生物学。根据初步数据，我们的操作模型是Bcl6通过抑制-Of-TFH来控制TFH的分化 抑制器机制。将对可能的机制进行全面测试。目标2.目标1已确定和 将确定关键的Bcl6-r TF。在目标2中，我们探索了这些转铁蛋白的生物学和可能的机制 这些TF控制着TFH。目的3.转铁蛋白对B细胞的帮助是一个多方面的过程，其中许多方面尚不清楚 关于涉及的分子。这在一定程度上是因为它是一组复杂的函数，还有一部分原因是 以前的技术限制。很可能，阐明肿瘤分化的免疫生物学基础 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性疾病的疫苗开发。