| First Author | Fedeli M | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 51 | Pages | E8286-E8295 |
| PubMed ID | 27930306 | Mgi Jnum | J:357963 |
| Mgi Id | MGI:6869347 | Doi | 10.1073/pnas.1612024114 |
| Citation | Fedeli M, et al. (2016) miR-17 approximately 92 family clusters control iNKT cell ontogenesis via modulation of TGF-beta signaling. Proc Natl Acad Sci U S A 113(51):E8286-E8295 |
| abstractText | 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-betaRII), 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 approximately 92 family clusters were predicted to target Tgfbr2 mRNA upon iNKT cell development. iNKT cells lacking all three miR-17 approximately 92 family clusters (miR-17 approximately 92, miR-106a approximately 363, miR-106b approximately 25) phenocopied both increased TGF-betaRII 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. |
