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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：
8522152
负责人：
Alexander L Dent
金额：
$ 22万
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/8522152
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.

描述（由申请方提供）：CD 4 T辅助细胞对于免疫应答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。滤泡辅助性T（Tfh）细胞是最近表征的CD 4 T细胞亚群，其作用是特异性地帮助B细胞产生抗体，部分通过促进生发中心反应。在缺乏Tfh细胞的情况下，生发中心和二次抗体反应不能发展。Tfh细胞的过度发育可导致自身免疫。Tfh细胞由于其表达趋化因子受体CXCR 5而定位于B细胞滤泡。Tfh细胞的特征还在于转录阻遏物BCL 6的高表达和B细胞刺激性细胞因子IL-21的分泌。最近的研究表明，BCL 6是Tfh细胞的主要转录调节因子：强制BCL 6表达可以诱导T细胞中的Tfh表型，并且Tfh细胞在没有BCL 6的情况下不能发育。然而，Tfh细胞的研究缺乏的是用于分析Tfh细胞功能的方便的体内系统。虽然BCL 6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。我们目前正在开发小鼠，其中BCL 6在CD 4 T细胞中特异性突变。我们建议，这种小鼠模型将是非常有用的，大大改善模型的研究Tfh细胞的功能。此外，该小鼠将提供Tfh细胞内在地依赖于BCL 6以用于其发育的基本和最终确认。创新：这项研究使用了一种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：这些实验将提供信息，这是了解抗体反应的发展，以打击传染病的关键。这些研究还应该加速靶向Tfh细胞的疫苗的开发，以及对自身抗体产生的影响研究。