Montoya Misty M, Maul Julia, Singh Priti B, Pua Heather H, Dahlström Frank, Wu Nanyan, Huang Xiaozhu, Ansel K Mark, Baumjohann Dirk
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143.
Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, 82152 Planegg-Martinsried, Germany.
J Immunol. 2017 Jul 15;199(2):559-569. doi: 10.4049/jimmunol.1700170. Epub 2017 Jun 12.
Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6 RAR-related orphan receptor (ROR)γt Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in mouse and human CD4 T cells, revealing functional conservation. miR-18a directly targeted , , and , all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster.
辅助性T细胞17（Th17）细胞反应在协调针对细胞外病原体的免疫反应中发挥作用，但也是自身免疫性疾病发病机制的基础。在本研究中，我们发现微小RNA-18a（miR-18a）在限制Th17细胞分化方面具有独特且关键的作用。miR-18a是活化T细胞中miR-17-92簇中上调最为动态的微小RNA。miR-18a缺陷在体外增强了CC趋化因子受体6（CCR6）视黄酸相关孤儿受体（ROR）γt Th17细胞的分化，并在体内气道炎症模型中增加了表达CCR6、RORγt和白细胞介素-17A（IL-17A）的组织Th17细胞数量。序列特异性miR-18抑制剂增加了小鼠和人类CD4 T细胞中CCR6和RORγt的表达，揭示了功能保守性。miR-18a直接靶向Th17细胞基因表达程序中的所有关键转录因子，即 、 和 。这些发现表明，激活信号通过对一个共同簇内成熟微小RNA的差异调节来影响Th细胞分化的结果。
