Tie2cre-induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development.
MicroRNAs (miRNAs) are a class of evolutionarily conserved small noncoding RNAs that are increasingly being recognized as important regulators of gene expression. The ribonuclease III enzyme Dicer is essential for the processing of miRNAs. CD1d-restricted invariant natural killer T (iNKT) cells are potent regulators of diverse immune responses. The role of Dicer-generated miRNAs in the development and function of immune regulatory iNKT 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 iNKT cells in the thymus and significantly decreased the number of iNKT cells in different immune organs. Thymic and peripheral iNKT cell compartments were changed in miRNA-deficient mice, with a significantly increased frequency of CD4(+)CD8(+) iNKT cells in the thymus and a significantly decreased frequency of CD4(+) iNKT cells in the spleen. MiRNA-deficient iNKT cells display profound defects in alpha-GalCer-induced activation and cytokine production. Bone marrow (BM) from miRNA-deficient mice poorly reconstituted iNKT cells compared to BM from WT mice. Also, using a thymic iNKT cell transfer model, we found that iNKT 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 iNKT cell development, function, and homeostasis.
Zhou
Li
L
Henry Ford Immunology Program, and Department of Dermatology, Henry Ford Hospital, Detroit, MI 48202, USA.
Seo
Kook-Heon
KH
He
Hong-Zhi
HZ
Pacholczyk
Rafal
R
Meng
Dong-Mei
DM
Li
Chang-Gui
CG
Xu
Jianrui
J
She
Jin-Xiong
JX
Dong
Zheng
Z
Mi
Qing-Sheng
QS
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000201:enzymology / Q000276:immunology*; D042787:Receptor, TIE-2 / Q000235:genetics; D043244:Ribonuclease III; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D035683:MicroRNAs; D042787:Receptor, TIE-2; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases