Development of follicular helper T cell deficient mice

滤泡辅助性T细胞缺陷小鼠的发育

基本信息

批准号：
8289751
负责人：
Alexander L Dent
金额：
$ 19.5万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289751
关键词：
Affect Affinity Antibodies Antibody Formation Antigens Autoantibodies Autoimmunity B-Lymphocytes BCL6 gene BLR1 gene Breeding CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cell physiology Cells Communicable Diseases Defect Development Disease Gene Targeting Generations Helper-Inducer T-Lymphocyte Immune response In Vitro Knockout Mice Lead Mus Mutate Phenotype Production Reaction Regulatory T-Lymphocyte Role Staging Structure of germinal center of lymph node Study models System Systems Analysis T cell differentiation T-Cell Development T-Lymphocyte Testing Thymus Gland Transcription Repressor/Corepressor Transgenic Mice Transgenic Model Transgenic Organisms biological systems cell type chemokine receptor cytokine fighting improved in vivo innovation insight mouse model novel programs research study tool vaccine development

项目摘要

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.

描述（由申请人提供）：CD4 T 辅助细胞对于免疫反应的正常功能至关重要，并且对于帮助 B 细胞产生高亲和力抗原特异性抗体至关重要。滤泡辅助 T (Tfh) 细胞是最近鉴定的 CD4 T 细胞亚群，其作用是专门帮助 B 细胞产生抗体，部分是通过促进生发中心反应。在缺乏 Tfh 细胞的情况下，生发中心和二抗反应无法发展。 Tfh细胞的过度发育可导致自身免疫。 Tfh 细胞由于表达趋化因子受体 CXCR5 而定位于 B 细胞滤泡。 Tfh 细胞的另一个特点是高表达转录抑制因子 BCL6，并分泌 B 细胞刺激性细胞因子 IL-21。最近的研究表明，BCL6是Tfh细胞的主要转录调节因子：强制BCL6表达可以诱导T细胞出现Tfh表型，而Tfh细胞在没有BCL6的情况下无法发育。然而，Tfh细胞的研究缺乏的是一种方便的体内系统来分析Tfh细胞的功能。 BCL6基因敲除小鼠虽然缺乏Tfh细胞，但也存在大量其他缺陷，且难以繁殖。我们目前正在开发 CD4 T 细胞中 BCL6 发生特异性突变的小鼠。我们认为该小鼠模型对于 Tfh 细胞功能的研究将是非常有用且大大改进的模型。此外，该小鼠将提供必要且最终的确认，证明 Tfh 细胞的发育本质上依赖于 BCL6。创新：本研究使用全新的小鼠模型来分析 Tfh 细胞功能。此外，我们建议开发一种创新的转基因小鼠，可用于追踪 Tfh 细胞的命运。总体而言，这些实验将深入了解 Tfh 细胞的发育，并将导致开发用于研究 Tfh 细胞功能的重要新工具。影响：这些实验将为了解对抗传染病的抗体反应的发展提供至关重要的信息。这些研究还将加速针对 Tfh 细胞的疫苗的开发，并影响自身抗体生产的研究。公共卫生相关性：CD4 T 辅助细胞对于正确的免疫反应至关重要，CD4 T 细胞在帮助 B 细胞制造抗击疾病的抗原特异性抗体方面尤其重要。滤泡辅助 T (Tfh) 细胞是最近发现的 CD4 T 细胞亚群，其作用专门帮助 B 细胞产生抗体。在这里，我们建议开发和表征新的生物系统来研究 Tfh 细胞的分化和功能。