Development of follicular helper T cell deficient mice

描述(由申请人提供)：CD4T辅助细胞对免疫反应的正常功能至关重要，并且对于帮助B细胞制造高亲和力的抗原特异性抗体至关重要。滤泡辅助性T细胞(TFH)是最近鉴定的CD4T细胞亚群，其作用是帮助B细胞产生抗体，部分是通过促进生发中心反应。在没有TFH细胞的情况下，生发中心和二次抗体反应无法发展。TFH细胞过度发育可导致自身免疫。由于表达趋化因子受体CXCR5，TFH细胞定位于B细胞滤泡。TFH细胞还具有高表达转录抑制因子BCL6和分泌B细胞刺激因子IL-21的特点。最近的研究表明，BCL6是TFH细胞的主要转录调控因子：强迫表达BCL6可以在T细胞中诱导TFH表型，而TFH细胞在没有BCL6的情况下不能发育。然而，对TFH细胞的研究缺乏一个方便的在体系统来分析TFH细胞的功能。虽然BCL6基因敲除小鼠缺乏Tfh细胞，但它们也有大量其他缺陷，难以繁殖。我们目前正在开发BCL6在CD4T细胞中发生特异性突变的小鼠。我们认为，这种小鼠模型将是非常有用的和极大地改进的模型，以研究TFH细胞的功能。此外，这只小鼠将提供基本的和最终的确认，即TFH细胞的发育本质上依赖于BCL6。创新：这项研究使用了一种全新的小鼠模型来分析TFH细胞的功能。此外，我们建议开发一种创新的转基因小鼠，可以用来追踪TFH细胞的命运。总体而言，这些实验将对TFH细胞的发展有深入的了解，并将导致开发一种研究TFH细胞功能的关键新工具。影响：这些实验将提供对理解抗体反应的发展以对抗传染病至关重要的信息。这些研究还应加快针对TFH细胞的疫苗的开发，以及对自身抗体产生的影响研究。 公共卫生相关性：CD4T辅助细胞对于正确的免疫反应至关重要，而CD4T细胞在帮助B细胞制造抗病抗原特异性抗体方面尤为重要。滤泡辅助性T细胞(TFH)是最近发现的一种CD4T细胞亚群，其作用是特异性地帮助B细胞产生抗体。在这里，我们建议开发和表征新的生物学系统来研究TFH细胞的分化和功能。

DESCRIPTION (provided by applicant): CD4 T helper cells are critical for the proper function of the immune response and are essential for helping B cells make high affinity antigen-specific antibody. Follicular helper T (Tfh) cells are a recently characterized subset of CD4 T cells whose role is specifically to help B cells produce antibody, in part by promoting the germinal center reaction. In the absence of Tfh cells, germinal centers and secondary antibody responses fail to develop. Excessive development of Tfh cells can lead to autoimmunity. Tfh cells are localized to B cell follicles due to their expression of the chemokine receptor CXCR5. Tfh cells are also characterized by high expression of the transcription repressor BCL6, and secretion of the B cell stimulatory cytokine IL-21. Recent studies have shown that BCL6 is the master transcriptional regulator for Tfh cells: forced BCL6 expression can induce a Tfh phenotype in T cells, and Tfh cells cannot develop in the absence of BCL6. However, what is lacking for the study of Tfh cells is a convenient in vivo system for analyzing the function of Tfh cells. While BCL6 knockout mice lack Tfh cells, they also have a large number of other defects and are difficult to breed. We are currently developing mice in which BCL6 is specifically mutated in CD4 T cells. We propose that this mouse model will be highly useful and vastly improved model for the study of Tfh cell function. Furthermore, this mouse will provide essential and final confirmation that Tfh cells are intrinsically dependent upon BCL6 for their development. INNOVATION: This study uses a completely novel mouse model to analyze Tfh cell function. Additionally, we propose to develop an innovative transgenic mouse that can be used to track the Tfh cell fate. Overall, these experiments will give insights into the development of Tfh cells and will lead to the development of a critical new tool for studying Tfh cell function. IMPACT: These experiments will provide information that is critical for understanding the development of the antibody response to fight infectious disease. These studies should also accelerate the development of vaccines that target Tfh cells, as well as impact studies on autoantibody production. PUBLIC HEALTH RELEVANCE: CD4 T helper cells are critical for the proper immune response, and CD4 T cells are particularly important in helping B cells in make antigen-specific antibody that fights disease. Follicular helper T (Tfh) cells are a recently discovered subset of CD4 T cells whose role is specifically to help B cells produce antibody. Here we propose to develop and characterize novel biological systems to study Tfh cell differentiation and function.