Regulation of Tfh cell differentiation and humoral immunity

项目摘要 CD4+T滤泡辅助细胞(TFH)是生发中心(GC)应答和长期免疫应答所必需的细胞。 长期体液免疫。然而，决定TFH分化的复杂监管 细胞，它们在GC中的发育过程，以及它们在帮助GC B细胞中的数量和功能 分化和抗体亲和力的选择，目前仍不完全清楚。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 操纵体液反应治疗传染病和自身免疫性疾病，并 帮助疫苗开发。 最近，我们已经鉴定出转录因子Foxp1是一个限速性的临界负值 TFH细胞分化的调节因子，这极大地影响了TFH细胞分化的动力学和幅度 抗体反应。我们新的初步数据现在开始揭示Foxp1与一个复合体 协同抑制TFH细胞分化的调节因子网络以及TFH对B细胞的帮助 处于GC反应的不同阶段/步骤的细胞。在本应用程序中，我们的目标是识别Foxp1目标 阐明Foxp1调控TFH细胞分化的分子机制。此外, 我们将进一步阐明Foxp1介导的TfH细胞分化调节如何影响GC B细胞 发育、抗体亲和力选择和慢性感染。我们的研究不仅将揭示新的 转录调控成分在TFH细胞分化中也提供了基本的 调节GC B细胞反应和抗体亲和力选择的机械论见解。

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.