Regulation of T Follicular Helper Cell Differentiation by MicroRNAs

MicroRNA对T细胞分化的调控 肖长春，斯克里普斯研究所 项目摘要 T细胞的帮助对于体液免疫应答是必不可少的。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细胞的分化和功能是 对于产生高亲和力抗体和控制慢性病毒感染是必需的，而TFH细胞 在一部分自身免疫性疾病患者和几种小鼠模型中观察到了扩增 的自身免疫，并显示在某些模型中的疾病发病机制中发挥致病作用。 因此，阐明TFH细胞分化和凋亡的细胞和分子机制是非常重要的。 功能对于设计更好的疫苗和疗法至关重要， 在感染环境中产生抗体和在自身免疫中产生沉默抗体。在 初步研究发现，突变小鼠具有T细胞特异性缺失miR-17~92 一个由三个miRNA簇组成的家族，编码13种不同的miRNA， 严重损害了TFH分化、生发中心形成、抗体产生， 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)分析miR-17~92在TFH分化中的作用; 2）研究miR-17~92在TFH分化中的作用。 miR-17~92家族miRNAs调控TFH的分子和细胞途径 3）研究另外的miRNA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， 鉴定了四个在TFH细胞中高度表达的miRNA基因。我们已经获得了所有基因敲除小鼠 这些miRNA基因，并将使用它们来研究TFH的分化和功能。

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.