Deletion of miRNAs in bone morrow disrupts iNKT cell development and function (136.19)

Abstract

Abstract MicroRNAs (miRNAs), a class of non-coding small RNAs, function as endogenous translation repressors of protein-coding genes. Accumulated evidences indicate that miRNAs are differentially regulated in developmental hematopoietic organs during hematopoietic lineage differentiation. Invariant Natural Killer T (iNKT) cells are potent regulators of diverse immune responses. The role of miRNAs in iNKT cell development is unknown. Here we test if lack of miRNAs following the deletion of Dicer, the miRNAs-processing enzyme, will affect iNKT cell development and function. We generated a mouse strain with tissue-specific disruption of Dicer in the hematopoietic progenitors, which is designated as Dicerfl/flTie2Cre+ (Dicer KO). Significantly decreased iNKT cell ratio and munber were found in the thymus, spleen, and liver of Dicer KO mice compared to littermate control (Dicerfl/flTie2cre-). The frequencies of mature CD44hiNK-1.1+ iNKT cells were significantly decreased in Dicer KO mice, suggesting that miRNAs may regulate iNKT cell maturation at the CD44low to CD44hi and NK1.1- to NK1.1+ checkpoints. Furthermore, miRNA-deficient peripheral iNKT cells display profound defects in alpha-GalCer-induced activation and cytokine production. Bone marrow (BM) from Dicer KO mice poorly reconstituted iNKT cells compared to BM from WT control mice, while thymic iNKT cells from WT mice poorly migrate to liver and spleen in irradiated Dicer KO mice compared to that in WT control mice. In summary, miRNAs are potent regulators of iNKT cell development, migration, and function. (Supported by JDRF).