title: Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation.
abstract: Mir-17-92 encodes 6 miRNAs inside a single polycistronic transcript, the proper expression of which is critical for early B-cell development and lymphocyte homeostasis. However, during the T-cell antigen response, the physiologic function of endogenous miR-17-92 and the roles of the individual miRNAs remain elusive. In the present study, we functionally dissected the miR-17-92 cluster and revealed that miR-17 and miR-19b are the key players controlling Th1 responses through multiple coordinated biologic processes. These include: promoting proliferation, protecting cells from activation-induced cell death, supporting IFN-γ production, and suppressing inducible regulatory T-cell differentiation. Mechanistically, we identified Pten (phosphatase and tensin homolog) as the functionally important target of miR-19b, whereas the function of miR-17 is mediated by TGFβRII and the novel target CREB1. Because of its vigorous control over the Th1 cell-inducible regulatory T cell balance, the loss of miR-17-92 in CD4 T cells results in tumor evasion. Our results suggest that miR-19b and miR-17 could be harnessed to enhance the efficacy of T cell-based tumor therapy.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Chaoran
authors.initials: C
authors.lastname: Li
authors.forename: Virginie
authors.initials: V
authors.lastname: Olive
authors.forename: Erik
authors.initials: E
authors.lastname: Lykken
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.forename: Jose
authors.initials: J
authors.lastname: Sevilla
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D005810:Multigene Family; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology* / Q000502:physiology*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C561642:MIRN19 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D018125:Receptors, Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II