title: miR-155 Upregulation in Dendritic Cells Is Sufficient To Break Tolerance In Vivo by Negatively Regulating SHIP1.
abstract: TLR-induced maturation of dendritic cells (DCs) leads to the production of proinflammatory cytokines as well as the upregulation of various molecules involved in T cell activation. These are believed to be the critical events that account for the induction of the adaptive immune response. In this study, we have examined the role of miR-155 in DC function and the induction of immunity. Using a model in which the transfer of self-Ag-pulsed, TLR-matured DCs can induce a functional CD8 T cell response and autoimmunity, we find that DCs lacking miR-155 have an impaired ability to break immune tolerance. Importantly, transfer of self- Ag-pulsed DCs overexpressing miR-155 was sufficient to break tolerance in the absence of TLR stimuli. Although these unstimulated DCs induced T cell function in vivo, there was no evidence for the upregulation of costimulatory ligands or cytokine secretion. Further analysis showed that miR-155 influenced the level of the phosphatase SHIP1 in DCs and that the lack of SHIP1 in DCs was sufficient to break T cell tolerance in vivo, again in the absence of TLR-induced DC maturation. Our study demonstrates that the overexpression of miR-155 in DCs is a critical event that is alone sufficient to break self-tolerance and promote a CD8-mediated autoimmune response in vivo. This process is independent of the induction of conventional DC maturation markers, indicating that miR-155 regulation of SHIP represents a unique axis that regulates DC function in vivo.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada; Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR 97239;
authors.forename: Evan F
authors.initials: EF
authors.lastname: Lind
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Millar
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada; Department of Immunology, University of Toronto, University Health Network, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR 97239;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Savage
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Grimshaw
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210; and Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, NY 13210.
authors.forename: William G
authors.identifier: http://orcid.org/0000-0002-4720-7135
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada; Department of Immunology, University of Toronto, University Health Network, Toronto, Ontario M5G 2C1, Canada; pohashi@uhnres.utoronto.ca.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases