Pobezinsky Leonid A, Etzensperger Ruth, Jeurling Susanna, Alag Amala, Kadakia Tejas, McCaughtry Tom M, Kimura Motoko Y, Sharrow Susan O, Guinter Terry I, Feigenbaum Lionel, Singer Alfred
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA.
Nat Immunol. 2015 May;16(5):517-24. doi: 10.1038/ni.3146. Epub 2015 Apr 6.
Lethal-7 (let-7) microRNAs (miRNAs) are the most abundant miRNAs in the genome, but their role in developing thymocytes is unclear. We found that let-7 miRNAs targeted Zbtb16 mRNA, which encodes the lineage-specific transcription factor PLZF, to post-transcriptionally regulate PLZF expression and thereby the effector functions of natural killer T cells (NKT cells). Dynamic upregulation of let-7 miRNAs during the development of NKT thymocytes downregulated PLZF expression and directed their terminal differentiation into interferon-γ (IFN-γ)-producing NKT1 cells. Without upregulation of let-7 miRNAs, NKT thymocytes maintained high PLZF expression and terminally differentiated into interleukin 4 (IL-4)-producing NKT2 cells or IL-17-producing NKT17 cells. Upregulation of let-7 miRNAs in developing NKT thymocytes was signaled by IL-15, vitamin D and retinoic acid. Such targeting of a lineage-specific transcription factor by miRNA represents a previously unknown level of developmental regulation in the thymus.
致死-7（let-7）微小RNA（miRNA）是基因组中最丰富的miRNA，但它们在胸腺细胞发育中的作用尚不清楚。我们发现，let-7 miRNA靶向Zbtb16 mRNA，该mRNA编码谱系特异性转录因子PLZF，以转录后方式调节PLZF表达，从而调节自然杀伤T细胞（NKT细胞）的效应功能。在NKT胸腺细胞发育过程中，let-7 miRNA的动态上调下调了PLZF表达，并引导它们终末分化为产生干扰素-γ（IFN-γ）的NKT1细胞。如果没有let-7 miRNA的上调，NKT胸腺细胞会维持高PLZF表达，并终末分化为产生白细胞介素4（IL-4）的NKT2细胞或产生白细胞介素17的NKT17细胞。IL-15、维生素D和视黄酸会促使发育中的NKT胸腺细胞上调let-7 miRNA。miRNA对谱系特异性转录因子的这种靶向作用代表了胸腺中一种以前未知的发育调控水平。
