Transcriptional Regulation of CD4+ T Cell Differentiation and Diversified Memory

CD4 T 细胞分化和多样化记忆的转录调控

基本信息

批准号：
10741301
负责人：
Hui Hu
金额：
$ 32.5万
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：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10741301
关键词：
ATAC-seq Autoimmune Diseases B-Lymphocytes BACH2 gene BLR1 gene Biological Models CD4 Positive T Lymphocytes Cell Differentiation process Cells Chromatin Complex Data Development Generations Goals Helper-Inducer T-Lymphocyte Humoral Immunities IL2RA gene Immune response Immunization Inflammatory Interleukin-6 Knowledge Maintenance Maps Memory Modeling Molecular Mus Pathway interactions Population Positioning Attribute Process Proteins Regulation Reporter Research Role Structure of germinal center of lymph node T cell differentiation T cell response T memory cell T-Lymphocyte Subsets Transcriptional Regulation Vaccines Work arm cytokine cytotoxic design infectious disease treatment intraperitoneal memory CD4 T lymphocyte mouse model new pandemic novel novel marker novel therapeutic intervention pandemic potential programmed cell death protein 1 public health relevance receptor response single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing vaccine development

项目摘要

Project Summary 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, in particular, the initial CXCR5– versus CXCR5+ CD4+ T cell differentiation, the developmental progression of CXCR5+CD4+ T cells to become GC-Tfh cells, and the generation of follicular helper- like memory CD4+ T cells expressing CXCR5, are still not fully understood. Our proposal aims to fill in these knowledge gaps with long-term goals to identify novel pathways underlying the differentiation of CD4+ T cells. In our preliminary studies, we have discovered a novel network engaging various factors/pathways that fine-tunes CXCR5+ versus CXCR5– CD4+ T cell differentiation and regulates the generation of cytotoxic CD4+ T cells in the early stage of CD4+ T cell response. By combining RNA- seq, ATAC-seq, and single cell RNA-seq, our preliminary data also suggest that the PD-1+CXCR5+ pre-Tfh cells undergo substantial further differentiation to become PD-1hiCXCR5hi GC-Tfh cells. Additionally, we have generated novel “fate-mapping” reporter mice that will allow us to track the varied CXCR5– and CXCR5+ memory CD4+ T cells. Thus, in this application, we aim to dissect the molecular underpinning of the early stage CXCR5+ versus CXCR5– CD4+ T cell differentiation as well as to elucidate the mechanisms underlying the pre- to GC-Tfh differentiation and the generation of diversified CD4+ T cell memory. Our work will have a profound impact on the field of CD4+ T cell differentiation. The research will not only shed new light on our understanding of the mechanisms underlying the multiple steps of Tfh cell differentiation but also establish new model systems for memory CD4+ T cell studies. This proposal has the potential to provide important knowledge on how to control both the humoral and the cellular arms of the CD4+ T cell response for the treatment of infectious diseases and autoimmune disorders and how to aid vaccine development for new pandemic threats.

项目摘要 T卵泡辅助器（TFH）细胞对于生发中心（GC）的反应至关重要，并且长期体液免疫。然而，确定TFH细胞分化的复杂调节，在特别是，初始CXCR5 –与CXCR5+ CD4+ T细胞分化，发育 CXCR5+ CD4+ T细胞的进展成为GC-TFH细胞，并产生卵泡辅助器 - 像记忆CD4+ T细胞表达CXCR5一样，仍未完全了解。我们的建议旨在填补这些知识差距具有长期目标，以识别差异化的基础的新颖途径 CD4+ T细胞。在我们的初步研究中，我们发现了一个新颖的网络，吸引了各种微型CXCR5+与CXCR5 – CD4+ T细胞分化的因素/途径，并调节在CD4+ T细胞反应的早期阶段生成细胞毒性CD4+ T细胞。通过结合RNA- SEQ，ATAC-SEQ和单细胞RNA-Seq，我们的初步数据还表明PD-1+CXCR5+ TER-TFH细胞经历了实质性的进一步分化，成为PD-1HICXCR5HI GC-TFH细胞。此外，我们生成了小说的“命运映射”记者小鼠，这将使我们能够跟踪 CXCR5 - 和CXCR5+内存CD4+ T细胞的变化。在此应用中，我们旨在剖析早期CXCR5+与CXCR5 – CD4+ T细胞分化的分子基础为了阐明GC-TFH分化前的机制和生成多样化的CD4+ T细胞存储器。我们的工作将对CD4+ T细胞分化领域产生深远的影响。研究不仅会为我们对我们对多个步骤的机制的理解提供新的启示 TFH细胞分化，但还建立了用于记忆CD4+ T细胞研究的新模型系统。这提案有潜力提供有关如何控制体液和的重要知识 CD4+ T细胞反应的细胞臂治疗传染病和自身免疫性疾病以及如何帮助疫苗开发新的大流行威胁。