Pua Heather H, Steiner David F, Patel Sana, Gonzalez Jeanmarie R, Ortiz-Carpena Jorge F, Kageyama Robin, Chiou Ni-Ting, Gallman Antonia, de Kouchkovsky Dimitri, Jeker Lukas T, McManus Michael T, Erle David J, Ansel K Mark
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Immunity. 2016 Apr 19;44(4):821-32. doi: 10.1016/j.immuni.2016.01.003. Epub 2016 Feb 2.
MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27, miRNAs coexpressed from two genomic clusters, which each functioned independently to limit interleukin-4 (IL-4) production. Mice lacking both clusters in T cells displayed increased Th2 cell responses and tissue pathology in a mouse model of asthma. Gene expression and pathway analyses placed miR-27 upstream of genes known to regulate Th2 cells. They also identified targets not previously associated with Th2 cell biology which regulated IL-4 production in unbiased functional testing. Thus, elucidating the biological function and target repertoire of miR-24 and miR-27 reveals regulators of Th2 cell biology.
微小RNA（miRNA）是免疫反应中细胞命运决定的重要调节因子。它们通过协同抑制多个靶基因发挥作用，我们利用这一特性揭示了调控辅助性T细胞2（Th2）的调控网络。对原代T细胞中单个miRNA进行功能筛选，发现多个miRNA可抑制Th2细胞分化。其中包括miR-24和miR-27，这两种miRNA从两个基因组簇共表达，各自独立发挥作用以限制白细胞介素-4（IL-4）的产生。在哮喘小鼠模型中，T细胞中缺乏这两个簇的小鼠表现出增强的Th2细胞反应和组织病理学变化。基因表达和通路分析表明miR-27位于已知调控Th2细胞的基因上游。这些分析还鉴定出了以前与Th2细胞生物学无关的靶标，这些靶标在无偏差功能测试中调节IL-4的产生。因此，阐明miR-24和miR-27的生物学功能和靶标库揭示了Th2细胞生物学的调节因子。
