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

 描述(由申请人提供)：有效疫苗开发的主要目标是最大限度地产生保护性抗体反应，并发展持久的体液免疫。生发中心(GC)反应是体液免疫的标志，涉及B细胞和T细胞之间的紧密相互作用。具体地说，一个特殊的T细胞亚群，滤泡帮助T(TFH)细胞，被证明在为GC B细胞提供关键帮助方面发挥关键作用，从而使它们能够分化为高亲和力产生抗体的浆细胞和记忆B细胞。到目前为止，GcB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microRNAs(MiRNAs)。像转录因子一样，最近对miRNAs作用的研究表明，它们可以在免疫系统中作为重要的分子调节因子。miRNAs是小调节RNA物种的一个子集。我们的初步研究表明，缺乏miR-146a的小鼠表现出增强的GC反应，这表明miR-146a在控制GC反应中具有负调控作用。miR-146a是一种在GC B细胞和Tfh细胞中高表达的miRNA。在这里，我们提出了一项多方面的研究，采用遗传学、生化、免疫学和全动物实验的方法，全面研究miR-146a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建立miR-146a消融的新小鼠模型，我们将研究miR-146a在控制特定免疫细胞群中的GC反应中的作用。在分子水平上，我们将研究已知的miR-146a靶标，并识别有助于miR-146a调节的GC反应的新关键分子。总之，这项拟议的研究将极大地提高我们对依赖T细胞的体液免疫关键阶段中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成功的策略，旨在针对免疫系统中miRNA介导的基因调控机制，针对广泛的入侵微生物产生强大和持久的免疫反应。

 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.