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：
10714458
负责人：
Hui Hu
金额：
$ 50.79万
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：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714458
关键词：
ATAC-seq Autoimmune Diseases B-Lymphocytes BACH2 gene BLR1 gene Biological Models CD4 Positive T Lymphocytes Cell Differentiation process Cells Chromatin Communicable Diseases Complex Data Development Generations Genes 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 pandemic potential pandemic response programmed cell death protein 1 public health relevance receptor response single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing vaccine development vaccine strategy

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 genes/pathways underlying the CD4+ T cell differentiation. 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 to aid vaccine development for new pandemic threats and help the treatment of infectious diseases and autoimmune disorders.

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，发育进展 CXCR5+ CD4+ T细胞的of成为GC-TFH细胞，并产生卵泡辅助辅助记忆表达CXCR5的CD4+ T细胞仍未完全了解。我们的建议旨在填补这些具有长期目标的知识差距，以识别CD4+ T细胞的基因/途径分化。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+ pre-tfh 细胞经历了实质性的进一步分化，成为PD-1HICXCR5HI GC-TFH细胞。另外，我们已经产生了新颖的“命运”记者小鼠，这将使我们能够跟踪各种的CXCR5-和 CXCR5+内存CD4+ T细胞。在此应用中，我们旨在剖析分子基础早期CXCR5+与CXCR5 – CD4+ T细胞分化以及阐明 GC-TFH分化前的基础机制和多样化的CD4+ T细胞的产生记忆。我们的工作将对CD4+ T细胞分化领域产生深远的影响。研究将不仅为我们对TFH多个步骤的机制的理解提供了新的启示细胞分化，但还建立了用于记忆CD4+ T细胞研究的新模型系统。这个建议有潜力提供有关如何控制体液和细胞的重要知识 CD4+ T细胞反应的臂，以帮助疫苗开发新的大流行威胁，并帮助治疗传染病和自身免疫性疾病。