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.

项目摘要 CD4+ T滤泡辅助器（TFH）细胞对于生发中心（GC）反应至关重要，并且很长术语的体液免疫。但是，决定TFH分化的复杂调节细胞，它们在GC中的发育进展以及它们在帮助GC B细胞中的数量和功能分化和抗体亲和力选择仍未完全了解。我们的长期目标是确定TFH细胞分化的基础的新型途径，并设计新策略操纵体液反应以治疗传染病和自身免疫性疾病，并辅助疫苗开发。最近，我们将转录因子FOXP1确定为限制和临界负数 TFH细胞分化的调节剂，这极大地影响了动力学和大小抗体反应。我们的新初步数据现在开始揭示FOXP1参与复杂协调以抑制TFH细胞分化以及TFH有助于B的调节器网络细胞处于GC响应的不同阶段/步骤。在此应用程序中，我们旨在确定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细胞分化的调节如何影响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，但也提供基本在调节GC B细胞反应和抗体亲和力选择的机理见解。