title: Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation.
abstract: Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4(+) T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4(+) T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer "retinoic acid", and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs.
authors.affiliation: Helmholtz Zentrum München, Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Munich, Germany.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Warth
authors.affiliation: Helmholtz Zentrum München, Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Munich, Germany.
authors.forename: Kai P
authors.initials: KP
authors.lastname: Hoefig
authors.affiliation: Helmholtz Zentrum München, Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Munich, Germany.
authors.forename: Anian
authors.initials: A
authors.lastname: Hiekel
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schallenberg
authors.affiliation: Institute for Immunology, University of Munich, Munich, Germany.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Jovanovic
authors.affiliation: Institute for Immunology, University of Munich, Munich, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kretschmer
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Ansel
authors.affiliation: Helmholtz Zentrum München, Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Munich, Germany Institute for Immunology, University of Munich, Munich, Germany vigo.heissmeyer@med.uni-muenchen.de.
authors.forename: Vigo
authors.initials: V
authors.lastname: Heissmeyer
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; C569259:MIRN10 microRNA, mouse; D035683:MicroRNAs; C529101:Mirn150 microRNA, mouse; C573158:Mirn99 microRNA, mouse; D049452:Green Fluorescent Proteins; D014212:Tretinoin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Treg cells; T‐cell differentiation; miRNA function