title: Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver.
abstract: Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany &Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Volckmar
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany &Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Gereke
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Riese
authors.affiliation: Intravital Microscopy in Infection and Immunity, Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Philipsen
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Institute of Molecular Immunology, Technische Universität München, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wohlleber
authors.affiliation: Department of Veterinary Medicine, Institute of Veterinary Pathology, Free University Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Klopfleisch
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany &Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Stegemann-Koniszewski
authors.affiliation: Intravital Microscopy in Infection and Immunity, Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Müller
authors.affiliation: Department of Veterinary Medicine, Institute of Veterinary Pathology, Free University Berlin, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Institute of Molecular Immunology, Technische Universität München, Germany.|Institute of Molecular Medicine and Experimental Immunology, Universität Bonn, Germany.
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzman
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany &Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Medical Faculty of the Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007114:Immunization / Q000379:methods*; D037181:Lectins, C-Type / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D010047:Ovalbumin