Transcriptional Regulation of CD4+ T Cell Differentiation and Diversified Memory

项目摘要 T滤泡辅助细胞(TFH)对于生发中心(GC)的反应和长期的 体液免疫。然而，决定TFH细胞分化的复杂调控，在 特别是，最初的CXCR5-与CXCR5+CD4+T细胞分化，发育 CXCR5+CD4+T细胞向GC-Tfh细胞分化及卵泡辅助性T细胞的生成 像记忆中表达CXCR5的CD4+T细胞一样，目前仍不完全清楚。我们的提案旨在填补 这些知识差距具有长期目标，以确定潜在的分化的新途径 CD4+T细胞。 在我们的初步研究中，我们发现了一个新的网络，涉及不同的 微调CXCR5+与CXCR5-CD4+T细胞分化并调节 在早期阶段产生细胞毒性的CD4+T细胞反应。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细胞经过大量的进一步分化成为PD-1hiCXCR5hi GC-Tfh细胞。 此外，我们还创造了新的“命运地图”报告老鼠，这将使我们能够追踪 不同的CXCR5-和CXCR5+记忆性CD4+T细胞。因此，在本应用程序中，我们的目标是剖析 早期CXCR5+与CXCR5-CD4+T细胞分化的分子基础 为了阐明Pre-to GC-Tfh分化和产生的机制 多样化的CD4+T细胞记忆。 我们的工作将对CD4+T细胞分化领域产生深远的影响。这项研究 将不仅为我们对多个步骤背后的机制的理解提供新的线索 TFH细胞分化也为记忆性CD4+T细胞研究建立了新的模型体系。这 建议有可能提供重要的知识，如何控制幽默和 用于治疗感染性疾病和自身免疫的CD4+T细胞反应的细胞臂 以及如何为应对新的大流行威胁协助疫苗开发。

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.