Development of follicular helper T cell deficient mice

描述（由申请人提供）：CD4 T辅助细胞对免疫反应的正常功能至关重要，对帮助B细胞产生高亲和力抗原特异性抗体至关重要。滤泡辅助性T细胞（Tfh）是CD4 T细胞的一个新亚型，其作用是通过促进生发中心反应来帮助B细胞产生抗体。在缺乏Tfh细胞的情况下，生发中心和二抗反应不能发展。Tfh细胞的过度发育可导致自身免疫。Tfh细胞由于其趋化因子受体CXCR5的表达而定位于B细胞卵泡。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的特征。最近的研究表明，BCL6是Tfh细胞的主要转录调节因子：强制BCL6表达可在T细胞中诱导Tfh表型，而在缺乏BCL6的情况下Tfh细胞无法发育。然而，对于Tfh细胞的研究，缺乏一种方便的体内系统来分析Tfh细胞的功能。虽然BCL6基因敲除小鼠缺乏Tfh细胞，但它们也存在大量其他缺陷，难以繁殖。我们目前正在开发CD4 T细胞中BCL6特异性突变的小鼠。我们认为该小鼠模型将为Tfh细胞功能的研究提供一个非常有用的模型。此外，该小鼠将提供必要和最终的证实，Tfh细胞在其发育过程中本质上依赖于BCL6。创新：本研究使用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，可用于跟踪Tfh细胞的命运。总的来说，这些实验将深入了解Tfh细胞的发育，并将导致研究Tfh细胞功能的关键新工具的开发。影响：这些实验将为了解抗体反应的发展提供至关重要的信息，以对抗传染病。这些研究还应加速开发针对Tfh细胞的疫苗，以及对自身抗体产生的影响研究。

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.