Effector and memory T follicular helper cells

描述(由申请人提供)：T细胞依赖抗体的产生是宿主防御各种感染的关键机制。在生发中心发现了一种新的CD4T细胞亚群，称为T滤泡辅助细胞(TFH)，可通过其趋化因子(C-X-C基序)受体5(CXCR5)的表达来鉴定。除了CXCR5，TFH细胞的其他标志物也被报道，如共刺激受体ICOS、PD-1和BTLA、IL-21细胞因子和Bcl-6转录因子。与其他两个小组同时，陈东小组先前表明，Bcl6在T细胞介导的生发中心反应中起着不可或缺的作用；T细胞Bcl6缺陷小鼠在生发中心反应中受损。最近，使用一只新的Bcl6报告鼠，他们发现T细胞中最初的CXCR5上调先于Bcl6，并不依赖于Bcl6。在免疫反应之后，Bcl6记忆T细胞被产生。海琪小组使用双光子活体显微镜广泛地表征了TFH细胞在生发中心的定位和运动。我们建议本研究了解在感染性疾病中控制TFH细胞生成和记忆分化的遗传因素。中心假设是，不同的转录因子依次促进毛囊归巢、B细胞相互作用和GC定位程序的启动、维持和记忆形成，这些程序具有以下特征 TFH在传染病中的血统。我们将在三个具体目标下解决这一假设。具体目标1，我们将了解T细胞中CXCR5最初上调的机制。特别是，我们将研究我们最近发现的ASCL2转录因子的作用 在TFH细胞中上调，并足以诱导CXCR5的表达。具体目的2，我们将研究Bcl6在TFH细胞发育中的作用。我们将研究是否需要Bcl6来正确定位T细胞及其与B细胞的相互作用。此外，还将寻找Bcl6的直接目标。具体目标3，我们将研究记忆TFH细胞产生的机制。我们将分析存储器TFH单元生成和维护所需的因素。总体而言，我们建议的研究结合了陈东和海琪实验室在TFH细胞方面的独特专业知识。通过使用新的遗传和成像工具，我们在定义TFH细胞生成、功能和记忆分化的基本调控机制方面处于独特的地位。我们的工作结果可能有助于理解针对各种感染的体液免疫。

DESCRIPTION (provided by applicant): T cell-dependent antibody production is a critical mechanism in host defense to various infections. A new CD4+ T cell subset called T follicular helper (Tfh) cells were found to be present in germinal centers and could be identified by their expression of chemokine (C-X-C motif) receptor 5 (CXCR5). In addition to CXCR5, other markers have been also reported for Tfh cells, such as costimulatory receptors ICOS, PD-1 and BTLA, IL-21 cytokine and Bcl-6 transcription factor. Simultaneously with two other groups, Chen Dong group previously showed that Bcl6 serves an indispensable role in T cell-mediated germinal center reactions; mice with Bcl6 deficiency in T cells are impaired in germinal center reactions. More recently, using a new Bcl6 reporter mouse, they found that initial CXCR5 upregulation in T cells precedes that of Bcl6 and is not dependent on Bcl6. Following an immune response, Bcl6+ memory T cells are generated. Hai Qi group has used two-photon intravital microscopy to extensively characterize the localization and movement of Tfh cells in germinal centers. We propose for the current study to understand the genetic factors governing Tfh cell generation and memory differentiation in infectious diseases. The central hypothesis is that distinct transcription factors sequentially promote the initiation, maintenance, and memory formation of the follicle- homing, B cell-interacting, and GC-localizing programs that characterize the Tfh lineage in infectious diseases. We will address this hypothesis under three specific aims. Specific Aim 1, we will understand the mechanism underlying initial CXCR5 upregulation in T cells. In particular, we will study the role of ASCL2 transcription factor, which we recently found to be upregulated in Tfh cells and sufficient in inducing CXCR5 expression. Specific Aim 2, we will study Bcl6 function in Tfh cell development. We will study if Bcl6 is required for proper localization of T cells and their interaction with B cells. In addition, the direct targets of Bcl6will be sought. Specific Aim 3, we will investigate the mechanisms of memory Tfh cell generation. We will analyze the factors required for memory Tfh cell generation and maintenance. Overall, our proposed studies combine the unique expertise from Chen Dong and Hai Qi labs in Tfh cells. By using novel genetic and imaging tools, we are in a unique position in defining the fundamental regulatory mechanisms in Tfh cell generation, function and memory differentiation. The results from our work may help understand humoral immunity against various infections.