Development of follicular helper T cell deficient mice

滤泡辅助性T细胞缺陷小鼠的发育

• 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
• 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

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，对于帮助B细胞产生高亲和力抗原特异性抗体至关重要。卵泡辅助辅助剂T（TFH）细胞是最近表征的CD4 T细胞子集，其作用专门帮助B细胞产生抗体，部分通过促进生发中心反应。在没有TFH细胞的情况下，生发中心和二抗反应无法发展。 TFH细胞的过度发育会导致自身免疫性。 TFH细胞由于其表达趋化因子受体CXCR5而定位于B细胞卵泡。 TFH细胞还以转录阻遏物Bcl6的高表达和B细胞刺激细胞因子IL-21的分泌。最近的研究表明，BCL6是TFH细胞的主要转录调节剂：强迫BCL6表达可以诱导T细胞中的TFH表型，而在没有BCL6的情况下，TFH细胞无法发展。但是，研究TFH细胞缺乏的是用于分析TFH细胞功能的体内系统方便的。尽管Bcl6敲除小鼠缺乏TFH细胞，但它们也有大量其他缺陷，很难繁殖。我们目前正在开发在CD4 T细胞中特异性突变的小鼠。我们建议该小鼠模型将非常有用，并且可以大大改进TFH细胞功能的模型。此外，该小鼠将提供必不可少的最终确认，即TFH细胞本质上取决于Bcl6的发育。创新：这项研究使用完全新颖的小鼠模型来分析TFH细胞功能。此外，我们建议开发一种可用于跟踪TFH细胞命运的创新转基因小鼠。总体而言，这些实验将为TFH细胞的发展提供见解，并将导致开发研究TFH细胞功能的关键新工具。影响：这些实验将提供有关理解抗体反应对抗传染病的发展至关重要的信息。这些研究还应加速靶向TFH细胞的疫苗的发育，并影响对自身抗体产生的研究。 公共卫生相关性：CD4 T辅助细胞对于适当的免疫反应至关重要，CD4 T细胞对于帮助B细胞制造抗疾病的抗原特异性抗体尤为重要。卵泡辅助辅助剂T（TFH）细胞是最近发现的CD4 T细胞子集，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细胞分化和功能。