期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：E8286-E8295
DOI：10.1073/pnas.1612024114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes that play fundamental roles in cancer, autoimmunity, and infections. iNKT cells acquire effector functions already in the thymus, because of a distinct developmentally regulated genetic program that is critically controlled by miRNAs. Our study unveils the unexpected requirement for miRNA-dependent fine-tuning of TGF-{beta} signaling in the control of iNKT cell development and functional differentiation. The targeting of a lineage-specific cytokine signaling by miRNA represents a previously unknown level of developmental regulation in the thymus. Furthermore, our study provides a comprehensive atlas of miRNA-regulated molecular pathways involved in iNKT cell ontogenesis, and highlights molecular pathways targeted by defined miRNAs that are predicted to be involved in the development and maturation of CD1d-restricted iNKT cells. 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[~]92 family clusters were predicted to target Tgfbr2 mRNA upon iNKT cell development. iNKT cells lacking all three miR-17[~]92 family clusters (miR-17[~]92, miR-106a[~]363, miR-106b[~]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.
关键词：NKT cells ; miRNA ; TGF-β ; development ; CD1d
