title: In vivo targeting of human DC-SIGN drastically enhances CD8⁺ T-cell-mediated protective immunity.
abstract: Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8⁺ T-cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC-SIGN (DC-specific-ICAM3-grabbing-nonintegrin/CD209) is a C-type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC-SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC-SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti-DC-SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti-DC-SIGN antibodies conjugated to OVA induced strong and persistent antigen-specific CD4⁺ and CD8⁺ T-cell responses, which efficiently protected from infection with OVA-expressing Listeria monocytogenes. Thus, we propose DC targeting via DC-SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens.
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hesse
authors.forename: Wiebke
authors.initials: W
authors.lastname: Ginter
authors.forename: Theresa
authors.initials: T
authors.lastname: Förg
authors.forename: Christian T
authors.initials: CT
authors.lastname: Mayer
authors.forename: Abdul Mannan
authors.initials: AM
authors.lastname: Baru
authors.forename: Catharina
authors.initials: C
authors.lastname: Arnold-Schrauf
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.forename: Luciana
authors.initials: L
authors.lastname: Berod
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007110:Immunity, Active; D007111:Immunity, Cellular; D056747:Immunomodulation; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D014611:Vaccination; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D010047:Ovalbumin; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: Crosspresentation; DC-SIGN; Dendritic cells; Listeria; Vaccine