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 CXCR 5 + CD 4 + T细胞进展为GC-Tfh细胞，以及滤泡辅助细胞的产生。 例如表达CXCR 5的记忆性CD 4 + T细胞，仍然没有完全了解。我们的建议旨在填补 这些知识差距与长期目标，以确定新的途径的差异， CD 4 + T细胞。 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 + pre-Tfh细胞经历实质上的进一步分化以成为PD-1hiCXCR 5 hiGC-Tfh细胞。 此外，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这些小鼠。 改变CXCR 5-和CXCR 5+记忆CD 4 + T细胞。因此，在本申请中，我们的目标是剖析 早期CXCR 5+与CXCR 5-CD 4 + T细胞分化的分子基础 以阐明GC-Tfh分化前和GC-Tfh产生的潜在机制。 多样化的CD 4 + T细胞记忆 我们的工作将对CD 4 + T细胞分化领域产生深远的影响。研究 这不仅将为我们理解多个步骤的机制提供新的线索， Tfh细胞分化的研究，同时也为记忆性CD 4 + T细胞的研究建立了新的模型体系。这 该提案有可能提供关于如何控制体液和体液免疫的重要知识。 用于治疗感染性疾病和自身免疫性疾病的CD 4 + T细胞应答的细胞臂 疾病以及如何帮助疫苗开发以应对新的大流行威胁。

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.