Role of miR-146a at the interface between T and B cell immunity

miR-146a 在 T 细胞和 B 细胞免疫界面中的作用

• 批准号: 9223672
• 负责人: Li-Fan Lu
• 金额: $ 22.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-12 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223672
• 关键词: Ablation; Affinity; Animal Experimentation; Antibody Affinity; Antibody Response; Antigens; Automobile Driving; B-Cell Development; B-Lymphocytes; Biochemical; Cell surface; Cells; Cellular biology; Clonal Expansion; Computer Analysis; Development; Ensure; Exhibits; Frequencies; Gene Targeting; Generations; Genes; Genetic; Goals; High-Throughput Nucleotide Sequencing; Host Defense; Human; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunoglobulin Somatic Hypermutation; Immunologics; Immunoprecipitation; Invaded; Knowledge; Mediating; Mediator of activation protein; Memory B-Lymphocyte; MicroRNAs; Molecular; Mus; Pathogenicity; Phase; Phenotype; Pilot Projects; Plasma Cells; Play; Population; Production; RNA; Reaction; Regulation; Regulator Genes; Research; Role; Stimulus; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; Untranslated RNA; Up-Regulation; cell type; crosslink; crosslinking and immunoprecipitation sequencing; immunoregulation; improved; insight; member; microorganism; mouse model; novel; novel therapeutics; public health relevance; response; transcription factor; vaccine development

 DESCRIPTION (provided by applicant): The major goal of the effective vaccine development is to maximize the generation of protective antibody responses and to develop long-lasting humoral immunity. Germinal center (GC) reaction is the hallmark of humoral immunity involving tight interaction between B and T cells. Specifically, a specialized T cell subset, follicular helpr T (Tfh) cells, was shown to play pivotal roles in providing crucial help to GC B cells, thereby enabling them to differentiate into high affinity antibody-producing plasma cells and memory B cells. To date, GC B cells and Tfh cells were found to express many similar molecular features including cell surface molecules, transcription factors and microRNAs (miRNAs). Like transcription factors, recent studies investigating the role of miRNAs, a subset of small regulatory RNA species, have demonstrated that they can act as important molecular regulators in the immune system. Our preliminary studies have shown that mice devoid of miR-146a, a miRNA highly expressed in both GC B cells and Tfh cells, exhibited increased GC responses, suggesting a negative regulatory role of miR-146a in controlling GC reactions. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the role for miR-146a in T cell-dependent B cell-mediated humoral immunity. At the cellular level, by generating new mouse models with miR-146a ablation in different immune subsets, we will study the role of miR-146a in controlling GC responses in defined immune cell populations. At the molecular level, we will examine known miR-146a targets as well as identify new key molecules that contribute to miR-146a-regulated GC responses. Collectively, the proposed study will greatly improve our understanding of miRNA-mediated immune regulation during crucial phases of T cell-dependent humoral immunity. Ultimately, the long-term goal of our research is to develop successful strategies aimed at targeting miRNA-mediated gene regulatory machineries in the immune system to generate robust and long-lasting immune responses against a wide array of invading microorganisms.

 描述（由申请方提供）：有效疫苗开发的主要目标是最大限度地产生保护性抗体应答，并形成持久的体液免疫。免疫反应是体液免疫的重要标志，涉及B细胞和T细胞之间的紧密相互作用。特别是，一个专门的T细胞亚群，滤泡辅助T（Tfh）细胞，被证明在提供关键的帮助GC B细胞，从而使他们能够分化成高亲和力抗体产生的浆细胞和记忆B细胞中发挥关键作用。迄今为止，发现GC B细胞和Tfh细胞表达许多相似的分子特征，包括细胞表面分子、转录因子和microRNA（miRNAs）。与转录因子一样，最近研究miRNA（小调节RNA种类的一个子集）的作用的研究表明，它们可以在免疫系统中充当重要的分子调节剂。我们的初步研究表明，缺乏miR-146 a（一种在GC B细胞和Tfh细胞中高度表达的miRNA）的小鼠表现出增加的GC反应，表明miR-146 a在控制GC反应中的负调节作用。在这里，我们提出了一个多方面的研究，采用遗传学，生物化学，免疫学的方法和整体动物实验，全面检查miR-146 a在T细胞依赖的B细胞介导的体液免疫中的作用。在细胞水平上，通过在不同的免疫亚群中产生具有miR-146a消融的新小鼠模型，我们将研究miR-146a在确定的免疫细胞群体中控制GC应答的作用。在分子水平上，我们将研究已知的miR-146a靶点，并确定有助于miR-146a调节GC反应的新的关键分子。总的来说，这项研究将大大提高我们对T细胞依赖性体液免疫关键阶段miRNA介导的免疫调节的理解。最终，我们研究的长期目标是开发旨在靶向免疫系统中miRNA介导的基因调控机制的成功策略，以产生针对各种入侵微生物的强大且持久的免疫应答。