title: Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling.
abstract: Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c+dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity.
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Puttur
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany; Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Marcela
authors.initials: M
authors.lastname: Francozo
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Gülhas
authors.initials: G
authors.lastname: Solmaz
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany; Laboratorio de Virología, Departamento de Química Biológica, IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EGA, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Lindenberg
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gohmert
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Maxine
authors.initials: M
authors.lastname: Swallow
authors.affiliation: Department of Clinical Immunology and Rheumatology, MHH, 30625 Hannover, Germany.
authors.forename: Dejene
authors.initials: D
authors.lastname: Tufa
authors.affiliation: Department of Clinical Immunology and Rheumatology, MHH, 30625 Hannover, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Jacobs
authors.affiliation: Institute for Laboratory Animal Science, MHH, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; Institute for Experimental Infection Research, Twincore, MHH and HZI, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Medical Department (Gastroenterology, Infectious Diseases and Rheumatology)/Research Center ImmunoScience, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, HZI, 38124 Braunschweig, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Borkner
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, HZI, 38124 Braunschweig, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cicin-Sain
authors.affiliation: Department of Surgery, Technische Universität München, 81675 Munich, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Holzmann
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Berod
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany. Electronic address: tim.sparwasser@twincore.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D039521:CD11c Antigen / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000517:prevention & control* / Q000821:virology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D039521:CD11c Antigen; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma
keywords: MCMV; NK cells; TLR9-MyD88 signaling; conventional DC; plasmacytoid DC