Tie2cre-Induced Inactivation of the miRNA-Processing Enzyme Dicer Disrupts Invariant Nkt Cell Development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 25; pp. 10266 - 10271
• Main Authors: Zhou, Li, Seo, Kook-Heon, He, Hong-Zhi, Pacholczyk, Rafal, Meng, Dong-Mei, Li, Chang-Gui, Xu, Jianrui, She, Jin-Xiong, Dong, Zheng, Mi, Qing-Sheng, Marrack, Philippa
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.06.2009; National Acad Sciences
• Subjects: Animals; B lymphocytes; Biochemistry; Biological Sciences; Bone marrow; CD4 Antigens - immunology; CD8 Antigens - immunology; Cells; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Developmental biology; Endoribonucleases - genetics; Endoribonucleases - metabolism; Endothelial cells; Endothelial Cells - enzymology; Enzymes; Gene expression; Hematopoietic Stem Cells - enzymology; Liver; Lymphocyte Activation - genetics; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - metabolism; Natural killer T cells; Natural Killer T-Cells - enzymology; Natural Killer T-Cells - immunology; Receptor, TIE-2 - genetics; Ribonuclease III; Ribonucleic acid; RNA; Rodents; Spleen; T lymphocytes; Thymocytes; Thymus Gland - enzymology; Thymus Gland - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0811119106

MicroRNAs (miRNAs) are a class of evolutionarily conserved small noncoding RNAs that are increasingly being recognized as important regulators of gene expression. The ribonuclease lll enzyme Dicer is essential for the processing of miRNAs. CD 1d-restricted invariant natural killer T (/NKT) cells are potent regulators of diverse immune responses. The role of Dicer-generated miRNAs in the development and function of immune regulatory /NKT cells is unknown. Here, we generated a mouse strain with a tissue-specific disruption of Dicer, and showed that lack of miRNAs after the deletion of Dicer by Tie2-Cre (expressed in hematopoietic cells and endothelial cells) interrupted the development and maturation of /NKT cells in the thymus and significantly decreased the number of /NKT cells in different immune organs. Thymic and peripheral /NKT cell compartments were changed in miRNA-deficient mice, with a significantly increased frequency of CD4⁺ CD8⁺ /NKT cells in the thymus and a significantly decreased frequency of CD4⁺ /NKT cells in the spleen. MiRNA-defident /NKT cells display profound defects in α-GalCerinduced activation and cytokine production. Bone marrow (BM) from miRNA-deficient mice poorly reconstituted /NKT cells compared to BM from WT mice. Also, using a thymiciNKT cell transfer model, we found that /NKT cell homeostasis was impaired in miRNA-deficient recipient mice. Our data indicate that miRNAs expressed in hematopoietic cells and endothelial cells are potent regulators of /NKT cell development function, and homeostasis.