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

• 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
• 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

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.

项目概要 滤泡辅助 T (Tfh) 细胞对于生发中心 (GC) 反应和长期反应至关重要 体液免疫。然而，决定 Tfh 细胞分化的复杂调控，在 特别是，初始 CXCR5– 与 CXCR5+ CD4+ T 细胞分化、发育进程 CXCR5+CD4+ T 细胞成为 GC-Tfh 细胞，以及滤泡辅助记忆的产生 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 与识别 CD4+ T 细胞潜在新基因/通路的长期目标之间的知识差距 差异化。 在我们的初步研究中，我们发现了一个新颖的网络，涉及各种 微调 CXCR5+ 与 CXCR5– CD4+ T 细胞分化并调节 在 CD4+ T 细胞反应的早期阶段产生细胞毒性 CD4+ T 细胞。通过结合RNA-seq， ATAC-seq 和单细胞 RNA-seq，我们的初步数据也表明 PD-1+CXCR5+ pre-Tfh 细胞经历进一步实质性分化，成为 PD-1hiCXCR5hi GC-Tfh 细胞。此外，我们 已经培育出新型“命运图谱”报告小鼠，这将使我们能够追踪不同的 CXCR5 – 和 CXCR5+ 记忆 CD4+ T 细胞。因此，在本应用中，我们的目标是剖析分子基础 早期 CXCR5+ 与 CXCR5-CD4+ T 细胞分化的比较，并阐明 GC-Tfh 前分化和多样化 CD4+ T 细胞生成的机制 记忆。 我们的工作将对 CD4+ T 细胞分化领域产生深远的影响。该研究将 不仅让我们对 Tfh 多个步骤背后的机制有了新的认识 细胞分化，还为记忆 CD4+ T 细胞研究建立新的模型系统。这个提议 有潜力提供有关如何控制体液和细胞的重要知识 CD4+ T 细胞反应的武器，有助于针对新的大流行威胁的疫苗开发，并帮助 治疗传染病和自身免疫性疾病。