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miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Dec 20; Vol. 113 (51), pp. E8286-E8295. Date of Electronic Publication: 2016 Dec 05. - Publication Year :
- 2016
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Abstract
- 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-β receptor II (TGF-βRII), critically implicated in iNKT cell differentiation, was found up-regulated in iNKT Dicer KO cells together with enhanced TGF-β 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-βRII expression and signaling, and defective effector differentiation, displayed by iNKT Dicer KO cells. Consistently, genetic ablation of TGF-β 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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Antigens, CD1d metabolism
Cell Differentiation
Cytokines metabolism
DEAD-box RNA Helicases genetics
Gene Expression Profiling
Genetic Complementation Test
Mice
Mice, Inbred C57BL
Mice, Knockout
Multigene Family
Phenotype
RNA, Messenger metabolism
Ribonuclease III genetics
Signal Transduction
Thymus Gland metabolism
MicroRNAs genetics
Natural Killer T-Cells cytology
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 51
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27930306
- Full Text :
- https://doi.org/10.1073/pnas.1612024114