Regulation of Tfh cell differentiation and humoral immunity

Tfh细胞分化和体液免疫的调节

基本信息

批准号：
10165471
负责人：
Hui Hu
金额：
$ 49.16万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-05 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165471
关键词：
Affect Antibody Affinity Antibody Response Attenuated Autoimmune Diseases Autoimmunity B cell differentiation B-Cell Development B-Lymphocytes BACH2 gene BLR1 gene CD4 Positive T Lymphocytes CTLA4 gene Candidate Disease Gene Cell Count Cell Death Cell Differentiation process Cells Chronic Clinical Communicable Diseases Complex Data Development FOXP1 gene Goals Helper-Inducer T-Lymphocyte Humoral Immunities ITIM Immune response Kinetics Lead Mediating Messenger RNA Molecular Pathway interactions Play Proliferating Receptor Up-Regulation Regulation Role Signal Transduction Structure of germinal center of lymph node T-Cell Activation T-Lymphocyte Transcriptional Regulation Tumor stage Virus Diseases chronic infection design functional genomics infectious disease model infectious disease treatment insight novel novel marker overexpression programmed cell death protein 1 public health relevance receptor response transcription factor treatment response vaccine development vaccine trial

项目摘要

Project Summary CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) responses and long- term humoral immunity. However, the complex regulation that determines the differentiation of Tfh cells, their developmental progression in GC, and their number and function in helping GC B cell differentiation and antibody affinity selection, are still not fully understood. Our long-term goals are to identify novel pathways underlying the differentiation of Tfh cells and design new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders and to aid vaccine development. Recently we have identified transcription factor Foxp1 as a rate-limiting and critical negative regulator of Tfh cell differentiation, which drastically affects both the kinetics and the magnitude of the antibody responses. Our new preliminary data now start to reveal that Foxp1 engages a complex network of regulators that are coordinated to suppress Tfh cell differentiation as well as Tfh help to B cells at different stages/steps of the GC response. In this application, we aim to identify Foxp1 targets and elucidate the molecular mechanisms by which Foxp1 regulates Tfh cell differentiation. In addition, we will further delineate how Foxp1-mediated regulation of Tfh cell differentiation affects GC B cell development, antibody affinity selection and chronic infection. Our study will not only reveal new components of the transcriptional regulation in Tfh cell differentiation, but also provide fundamental mechanistic insights in the regulation of GC B cell responses and antibody affinity selection.

项目概要 CD4+ 滤泡辅助 T (Tfh) 细胞对于生发中心 (GC) 反应和长期免疫反应至关重要。术语“体液免疫”。然而，决定 Tfh 分化的复杂调控细胞、它们在 GC 中的发育进程，以及它们在帮助 GC B 细胞中的数量和功能分化和抗体亲和力选择仍不完全清楚。我们的长期目标是确定 Tfh 细胞分化的新途径并设计新策略操纵体液反应来治疗传染病和自身免疫性疾病，并援助疫苗研发。最近我们发现转录因子 Foxp1 是一个限速和关键阴性转录因子 Tfh 细胞分化的调节因子，极大地影响了 Tfh 细胞分化的动力学和幅度抗体反应。我们新的初步数据现在开始表明 Foxp1 涉及一个复杂的协调抑制 Tfh 细胞分化的调节因子网络以及 Tfh 有助于 B GC 响应不同阶段/步骤的细胞。在此应用中，我们的目标是识别 Foxp1 目标并阐明Foxp1调节Tfh细胞分化的分子机制。此外，我们将进一步描述 Foxp1 介导的 Tfh 细胞分化调节如何影响 GC B 细胞发育、抗体亲和力选择和慢性感染。我们的研究不仅会揭示新的 Tfh 细胞分化中转录调控的组成部分，而且还提供了基础 GC B 细胞反应调节和抗体亲和力选择的机制见解。