title: TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State.
abstract: Because of their unique capacity to cross-present Ags to CD8(+) T cells, mouse lymphoid tissue-resident CD8(+) dendritic cells (DCs) and their migratory counterparts are critical for priming antiviral T cell responses. High expression of the dsRNA sensor TLR3 is a distinctive feature of these cross-presenting DC subsets. TLR3 engagement in CD8(+) DCs promotes cross-presentation and the acquisition of effector functions required for driving antiviral T cell responses. In this study, we performed a comprehensive analysis of the TLR3-induced antiviral program and cell-autonomous immunity in CD8(+) DC lines and primary CD8(+) DCs. We found that TLR3-ligand polyinosinic-polycytidylic acid and human rhinovirus infection induced a potent antiviral protection against Sendai and vesicular stomatitis virus in a TLR3 and type I IFN receptor-dependent manner. Polyinosinic-polycytidylic acid-induced antiviral genes were identified by mass spectrometry-based proteomics and transcriptomics in the CD8(+) DC line. Nanostring nCounter experiments confirmed that these antiviral genes were induced by TLR3 engagement in primary CD8(+) DCs, and indicated that many are secondary TLR3-response genes requiring autocrine IFN-β stimulation. TLR3-activation thus establishes a type I IFN-dependent antiviral program in a DC subtype playing crucial roles in priming adaptive antiviral immune responses. This mechanism is likely to shield the priming of antiviral responses against inhibition or abrogation by the viral infection. It could be particularly relevant for viruses detected mainly by TLR3, which may not trigger type I IFN production by DCs that lack TLR3, such as plasmacytoid DCs or CD8(-) DCs.
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland;
authors.forename: Lajos
authors.initials: L
authors.lastname: Széles
authors.affiliation: Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany;
authors.forename: Felix
authors.initials: F
authors.lastname: Meissner
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland;
authors.forename: Christoph
authors.initials: C
authors.lastname: Thelemann
authors.affiliation: Computational Biology Group, Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland; and.
authors.forename: Micha
authors.initials: M
authors.lastname: Hersch
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland;
authors.forename: Simon
authors.initials: S
authors.lastname: Singovski
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland;
authors.forename: Sergio
authors.initials: S
authors.lastname: Haller
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland;
authors.forename: Florian
authors.initials: F
authors.lastname: Gobet
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland;
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Fuertes Marraco
authors.affiliation: Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Garcin
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland;
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; Walter.Reith@unige.ch.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010850:Picornaviridae Infections / Q000276:immunology / Q000821:virology; D011070:Poly I-C / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000276:immunology; D012229:Rhinovirus / Q000276:immunology; D029082:Sendai virus / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: C508032:Ifnar1 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011070:Poly I-C