title: miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling.
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.
authors.affiliation: Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Maya
authors.initials: M
authors.lastname: Fedeli
authors.affiliation: Genome Function Unit, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Riba
authors.affiliation: Genome Function Unit, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia Manteiga
authors.affiliation: Autoimmune Genetics Laboratory, Vlaams Instituut voor Biotechnologie, Katholieke Universiteit, 3000 Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Viganò
authors.affiliation: National Institute of Molecular Genetics, 20122 Milan, Italy.
authors.forename: Grazisa
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: National Institute of Molecular Genetics, 20122 Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Department of Immunology and Microbial Science; The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Changchun
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Autoimmune Genetics Laboratory, Vlaams Instituut voor Biotechnologie, Katholieke Universiteit, 3000 Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.affiliation: Genome Function Unit, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: Genome Function Unit, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Davide
authors.identifier: 0000-0003-0384-3700
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: National Institute of Molecular Genetics, 20122 Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: Genome Function Unit, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.|Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; dellabona.paolo@hsr.it casorati.giulia@hsr.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Dellabona
authors.affiliation: Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; dellabona.paolo@hsr.it casorati.giulia@hsr.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D055611:Natural Killer T-Cells / Q000166:cytology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics; D015398:Signal Transduction; D013950:Thymus Gland / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D016207:Cytokines; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: CD1d; NKT cells; TGF-β; development; miRNA