Regulation of Tfh cell differentiation and humoral immunity

项目摘要 CD 4+滤泡辅助性T细胞（Tfh）是生殖中心（GC）反应和长期免疫反应所必需的。 术语体液免疫。然而，决定Tfh分化的复杂调节 细胞，它们在GC中的发育进程，以及它们在帮助GC B细胞中的数量和功能 分化和抗体亲和力选择仍然没有完全理解。我们的长期目标是 确定Tfh细胞分化的新途径，并设计新的策略， 操纵体液应答以治疗感染性疾病和自身免疫性疾病， 帮助疫苗开发。 最近，我们已经确定转录因子Foxp 1作为一个限速和关键的负 Tfh细胞分化的调节剂，其显著影响Tfh细胞分化的动力学和大小。 抗体反应。我们新的初步数据现在开始揭示Foxp 1与一种复杂的 调节剂网络协调抑制Tfh细胞分化以及Tfh帮助B 在GC反应的不同阶段/步骤的细胞。在这个应用中，我们的目标是确定Foxp 1的目标， 阐明Foxp 1调控Tfh细胞分化的分子机制。此外，本发明还提供了一种方法， 我们将进一步阐明Foxp 1介导的Tfh细胞分化调控如何影响GC B细胞 发育、抗体亲和力选择和慢性感染。我们的研究不仅会揭示新的 Tfh细胞分化的转录调控成分，而且还提供了基本的 GC B细胞应答和抗体亲和力选择调节的机制见解。

Project Summary CD4+ 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, their developmental progression in GC, and their number and function in helping GC B cell differentiation and antibody affinity selection, are still not fully understood. Our long-term goals are to identify novel pathways underlying the differentiation of Tfh cells and design new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders and to aid vaccine development. Recently we have identified transcription factor Foxp1 as a rate-limiting and critical negative regulator of Tfh cell differentiation, which drastically affects both the kinetics and the magnitude of the antibody responses. Our new preliminary data now start to reveal that Foxp1 engages a complex network of regulators that are coordinated to suppress Tfh cell differentiation as well as Tfh help to B cells at different stages/steps of the GC response. In this application, we aim to identify Foxp1 targets and elucidate the molecular mechanisms by which Foxp1 regulates Tfh cell differentiation. In addition, we will further delineate how Foxp1-mediated regulation of Tfh cell differentiation affects GC B cell development, antibody affinity selection and chronic infection. Our study will not only reveal new components of the transcriptional regulation in Tfh cell differentiation, but also provide fundamental mechanistic insights in the regulation of GC B cell responses and antibody affinity selection.