Effector and memory T follicular helper cells

描述（由申请人提供）：T细胞依赖性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CD4+ T细胞亚群，称为T滤泡辅助细胞（Tfh），可以通过其趋化因子（C-X-C基序）受体5 （CXCR5）的表达来识别。除CXCR5外，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。与其他两组同时，陈东组先前发现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细胞缺乏Bcl6的小鼠生发中心反应受损。最近，他们使用一种新的Bcl6报告小鼠，发现T细胞中初始的CXCR5上调先于Bcl6上调，并且不依赖于Bcl6。在免疫应答后，Bcl6+记忆T细胞产生。海奇小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。我们建议在当前的研究中了解控制Tfh细胞产生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

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.