Effector and memory T follicular helper cells

效应和记忆滤泡辅助T细胞

• 批准号: 9040342
• 负责人: CHEN DONG
• 金额: $ 7.74万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040342
• 关键词: Effector; memory; follicular; helper; cells

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.

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 CD4+ T 细胞亚群，称为滤泡辅助 T (Tfh) 细胞，被发现存在于生发中心，可通过其趋化因子（C-X-C 基序）受体 5 (CXCR5) 的表达来识别。除了CXCR5之外，还报道了Tfh细胞的其他标志物，例如共刺激受体ICOS、PD-1和BTLA、IL-21细胞因子和Bcl-6转录因子。陈东课题组此前与另外两个课题组同时证明，Bcl6在T细胞介导的生发中心反应中发挥着不可或缺的作用； T 细胞中 Bcl6 缺陷的小鼠的生发中心反应受损。最近，使用新的 Bcl6 报告小鼠，他们发现 T 细胞中最初的 CXCR5 上调先于 Bcl6，并且不依赖于 Bcl6。免疫反应后，会产生 Bcl6+ 记忆 T 细胞。海琪课题组利用双光子活体显微镜广泛表征了Tfh细胞在生发中心的定位和运动。我们建议当前的研究了解控制传染病中 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 传染病中的 Tfh 谱系。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 细胞中初始 CXCR5 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 表达。具体目标2，我们将研究Bcl6在Tfh细胞发育中的功能。我们将研究 T 细胞的正确定位及其与 B 细胞的相互作用是否需要 Bcl6。此外，还将寻找Bcl6的直接靶点。具体目标3，我们将研究记忆Tfh细胞生成的机制。我们将分析记忆Tfh细胞生成和维持所需的因素。总的来说，我们提出的研究结合了 Chen Dong 和 Hai Qi 实验室在 Tfh 细胞方面的独特专业知识。通过使用新型遗传和成像工具，我们在定义 Tfh 细胞生成、功能和记忆分化的基本调节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。