Regulation of T Follicular Helper Cell Differentiation by MicroRNAs

MicroRNA 对滤泡辅助性 T 细胞分化的调节

• 批准号: 9204719
• 负责人: Changchun Xiao
• 金额: $ 13.09万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204719
• 关键词: Actins; Adoptive Transfer; Antibody Affinity; Antibody Formation; Antibody Response; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biochemical; Biological Process; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Chronic; Cytoskeleton; Disease; Evolution; Exhibits; Family; Generations; Genes; Genetic; Genetic study; Health; Helper-Inducer T-Lymphocyte; Immune response; Immune system; Immunology; Individual; Knockout Mice; LIMK1 gene; Length; Light; MicroRNAs; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Nature; Nucleotides; Pathogenesis; Pathway interactions; Patients; Play; Publishing; Reaction; Regimen; Regulation; Research; Research Institute; Role; Sequence Analysis; Signal Pathway; Small RNA; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Mice; Vaccine Therapy; Vaccines; Virus Diseases; base; cell motility; cofilin; deep sequencing; design; immunopathology; migration; mouse model; programs; therapeutic development

 DESCRIPTION (provided by applicant): Regulation of T Follicular Helper Cell Differentiation by MicroRNAs Changchun Xiao, The Scripps Research Institute Project Summary T cell help is essential for humoral immune responses. A distinct CD4+ effector T cell subset, T follicular helper cells (TFH), provides this help to B cells. TFH cell differentiation and function are essential for generation of high-affinity antibodies and control of chronic virus infection, while TFH cell expansion has been observed in a subset of autoimmune disease patients and several mouse models of autoimmunity, and was shown to play a causative role in disease pathogenesis in some models. Therefore, elucidating the cellular and molecular mechanisms underlying TFH cell differentiation and function is of critical importance for the design of better vaccines and therapies aimed to boost antibody production in infectious settings and mute antibody production in autoimmunity. In preliminary studies we have found that mutant mice with T cell-specific deletion of the miR-17~92 family, which consists of three miRNA clusters that encode thirteen distinct miRNAs, exhibited severely compromised TFH differentiation, germinal center formation, antibody production, and failed to control chronic virus infection. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated TFH cells and developed fatal immunopathology. In this proposal, we will: 1) Dissect the functions of individual miR-17~92 miRNAs in TFH differentiation; 2) Investigate the molecular and cellular pathways through which the miR-17~92 family miRNAs control TFH differentiation; 3) Investigate the roles of additional miRNAs in TFH differentiation and function. We have performed small RNA deep sequencing analysis of TFH cells sorted from immunized mice and identified four miRNA genes highly expressed in TFH cells. We have obtained knockout mice for all these miRNA genes and will use them to study TFH differentiation and function.

 描述（由申请人提供）：MicroRNA对T滤泡辅助细胞分化的调节长春肖，斯克里普斯研究所项目摘要T细胞辅助对体液免疫应答至关重要。一种独特的CD 4+效应T细胞亚群，T滤泡辅助细胞（TFH），为B细胞提供这种帮助。TFH细胞分化和功能对于产生高亲和力抗体和控制慢性病毒感染是必不可少的，而TFH细胞扩增已经在自身免疫性疾病患者的子集和几种自身免疫性小鼠模型中观察到，并且显示在一些模型中在疾病发病机制中起致病作用。因此，阐明TFH细胞分化和功能的细胞和分子机制对于设计更好的 疫苗和疗法旨在提高感染环境中的抗体产生，并抑制自身免疫中的抗体产生。在初步研究中，我们发现T细胞特异性缺失miR-17~92家族（由编码13种不同miRNA的3个miRNA簇组成）的突变小鼠表现出严重受损的TFH分化、生发中心形成、抗体产生，并且未能控制慢性病毒感染。相反，T 细胞特异性miR-17~92转基因小鼠自发积累TFH细胞并发展出致命的免疫病理学。在本提案中，我们将：1）研究miR-17~92家族miRNAs在TFH分化中的作用; 2）研究miR-17~92家族miRNAs调控TFH分化的分子和细胞途径; 3）研究其他miRNAs在TFH分化和功能中的作用。我们已经对从免疫小鼠中分选的TFH细胞进行了小RNA深度测序分析，并鉴定了四种在TFH细胞中高度表达的miRNA基因。我们已经获得了所有这些miRNA基因的敲除小鼠，并将使用它们来研究TFH的分化和功能。