miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling
miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling
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DOI：
10.1073/pnas.1612024114
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发表时间：
2016-12-20
影响因子：
11.1
通讯作者：
Casorati, Giulia
中科院分区：
文献类型：
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作者：
Fedeli, Maya;Riba, Michela;Casorati, Giulia
不变的天然杀伤细胞（INKT）细胞是T淋巴细胞，表现出具有先天效应子功能，这些函数是通过由microRNA（miRNA）调节的独特胸腺发育程序获得的。在胸腺细胞中通过dicer消融（DICER KO）删除miRNA，有选择地损害Inkt细胞的存活和功能分化。为了揭示这个依赖miRNA的程序，我们系统地识别出在不同分化阶段在WT和DICER KO INKT细胞之间差异表达的转录本，并被Inkt细胞特异性miRNA靶向。发现与Inkt细胞分化有关的TGF-β受体II（TGF-BETA RII）在Inkt Dicer KO细胞中上调，以及增强的TGF-BETA信号传导。 MiRNA的miRNA成员与92个家族簇相似，预计在Inkt细胞发育后靶向TGFBR2 mRNA。缺少所有三个miR-17的iNKT细胞类似于92个家族簇（MiR-17类似于92，miR-106a与363相似的miR-106a，miR-106b与25相似），均增加了TGF-Beta RII的表达和有缺陷的效应子差异化增加了，由inkt dicer ko细胞显示。一致地，在没有miRNA的情况下，TGF-β信号传导的遗传消融挽救了inkt细胞分化。这些结果阐明了miRNA对Inkt细胞发育程序的全球影响，并揭示了miRNA作为调节先天性T细胞发育和效应子分化的机制来靶向谱系特异性的细胞因子信号传导。
Invariant natural killer T cells (iNKT) cells are T lymphocytes displaying innate effector functions, acquired through a distinct thymic developmental program regulated by microRNAs (miRNAs). Deleting miRNAs by Dicer ablation (Dicer KO) in thymocytes selectively impairs iNKT cell survival and functional differentiation. To unravel this miRNA-dependent program, we systemically identified transcripts that were differentially expressed between WT and Dicer KO iNKT cells at different differentiation stages and predicted to be targeted by the iNKT cell-specific miRNAs. TGF-beta receptor II (TGF-beta RII), critically implicated in iNKT cell differentiation, was found up-regulated in iNKT Dicer KO cells together with enhanced TGF-beta signaling. miRNA members of the miR-17 similar to 92 family clusters were predicted to target Tgfbr2 mRNA upon iNKT cell development. iNKT cells lacking all three miR-17 similar to 92 family clusters (miR-17 similar to 92, miR-106a similar to 363, miR-106b similar to 25) phenocopied both increased TGF-beta RII expression and signaling, and defective effector differentiation, displayed by iNKT Dicer KO cells. Consistently, genetic ablation of TGF-beta signaling in the absence of miRNAs rescued iNKT cell differentiation. These results elucidate the global impact of miRNAs on the iNKT cell developmental program and uncover the targeting of a lineage-specific cytokine signaling by miRNAs as a mechanism regulating innate-like T-cell development and effector differentiation.