Transcriptional Regulation of CD4+ T Cell Differentiation and Diversified Memory

项目摘要 滤泡辅助性T细胞（Tfh）对于生殖中心（GC）反应和长期免疫应答是必不可少的。 体液免疫然而，决定Tfh细胞分化的复杂调控， 特别是，初始CXCR 5-与CXCR 5 + CD 4 + T细胞分化，发育进程， CXCR 5 + CD 4 + T细胞成为GC-Tfh细胞，并产生滤泡辅助样记忆 表达CXCR 5的CD 4 + T细胞仍然没有完全了解。我们的建议旨在填补这些 长期目标的知识差距，以确定新的基因/途径的CD 4 + T细胞 分化 在我们的初步研究中，我们发现了一个新的网络， 微调CXCR 5+与CXCR 5-CD 4 + T细胞分化的因子/途径， 在CD 4 + T细胞应答的早期阶段产生细胞毒性CD 4 + 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+ CXCR 5+前Tfh 细胞经历实质上的进一步分化以成为PD-1hiCXCR 5 hi GC-Tfh细胞。另外我们 已经产生了新的“命运映射”报告小鼠，这将使我们能够跟踪不同的CXCR 5-和 CXCR 5+记忆性CD 4 + T细胞。因此，在本申请中，我们的目标是剖析分子基础 早期CXCR 5+与CXCR 5-CD 4 + T细胞分化的关系，以及阐明 GC-Tfh前分化和多样化CD 4 + T细胞产生的机制 记忆 我们的工作将对CD 4 + T细胞分化领域产生深远的影响。这项研究将 不仅为我们理解Tfh多步骤的机制提供了新的线索， 细胞分化，而且还建立了新的模型系统的记忆CD 4 + T细胞的研究。这项建议 有可能提供关于如何控制体液和细胞免疫的重要知识。 CD 4 + T细胞反应的武器，以帮助疫苗开发新的大流行威胁，并帮助 治疗感染性疾病和自身免疫性疾病。

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.