Effector and memory T follicular helper cells

描述（由申请人提供）：T细胞依赖性抗体产生是宿主防御各种感染的关键机制。一种新的CD 4 + T细胞亚群，称为T滤泡辅助细胞（Tfh），被发现存在于生发中心，并可以通过其表达趋化因子（C-X-C基序）受体5（CXCR 5）来鉴定。除了CXCR 5，还报道了Tfh细胞的其他标志物，如共刺激受体ICOS、PD-1和BTLA、IL-21细胞因子和Bcl-6转录因子。同时与其他两个小组，陈东组先前表明，Bcl 6在T细胞介导的生发中心反应中起着不可或缺的作用; T细胞中Bcl 6缺陷的小鼠在生发中心反应中受损。最近，使用一种新的Bcl 6报告小鼠，他们发现T细胞中最初的CXCR 5上调先于Bcl 6，并且不依赖于Bcl 6。在免疫应答之后，产生Bcl 6+记忆T细胞。HaiQi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。我们建议目前的研究，以了解在感染性疾病中Tfh细胞生成和记忆分化的遗传因素。核心假设是不同的转录因子依次促进卵泡归巢、B细胞相互作用和GC定位程序的启动、维持和记忆形成，这些程序表征了 在传染病中的Tfh谱系。我们将在三个具体目标下讨论这一假设。具体目标1，我们将了解T细胞中初始CXCR 5上调的机制。特别是，我们将研究ASCL 2转录因子的作用，我们最近发现， 在Tfh细胞中上调并足以诱导CXCR 5表达。具体目标2：研究Bcl 6在Tfh细胞发育中的作用。我们将研究Bcl 6是否是T细胞正确定位及其与B细胞相互作用所必需的。此外，还将寻找Bcl 6的直接靶点。具体目标3，我们将研究记忆Tfh细胞的产生机制。我们将分析记忆Tfh细胞产生和维持所需的因素。总的来说，我们提出的研究联合收割机结合了Chen Dong和Hai Qi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，我们在确定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了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.