title: Targeting Influenza Virus Hemagglutinin to Xcr1+Dendritic Cells in the Absence of Receptor-Mediated Endocytosis Enhances Protective Antibody Responses.
abstract: Targeting Ags to conventional dendritic cells can enhance Ag-specific immune responses. Although most studies have focused on the induction of T cell responses, the mechanisms by which targeting improves Ab responses are poorly understood. In this study we present data on the use of human XCL1 (hXCL1) and hXCL2 fusion vaccines in a murine model. We show that the human chemokines bound type 1 conventional dendritic cells (cDC1), and that immunization with influenza virus hemagglutinin fused to hXCL1 or hXCL2 induced full protection against influenza challenge. Surprisingly, the hXCL1- and hXCL2-fusion vaccines induced better long-term protection associated with stronger induction of neutralizing Abs, and more Ab-secreting cells in bone marrow. In contrast, murine Xcl1 fusion vaccines induced stronger CD8+T cell responses compared with hXCL1. Further analysis revealed that although murine Xcl1 fusion vaccines induced chemotaxis and were rapidly endocytosed by cDC1, hXCL1 and hXCL2 fusion vaccines did not induce chemotaxis, were less efficiently endocytosed, and consequently, remained on the surface. This difference may explain the enhanced induction of Abs when targeting Ag to cDC1 using hXCL1 and hXCL2, and suggests that immune responses can be manipulated in directing Abs or T cells based on how efficiently the targeted Ag is endocytosed by the DC.
authors.affiliation: K.G. Jebsen Centre for Influenza Vaccine Research, University of Oslo and Oslo University Hospital, 0450 Oslo, Norway.
authors.forename: Arnar
authors.initials: A
authors.lastname: Gudjonsson
authors.affiliation: K.G. Jebsen Centre for Influenza Vaccine Research, University of Oslo and Oslo University Hospital, 0450 Oslo, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Lysén
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Marseille Cedex 09, France.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Sreekumar
authors.identifier: 0000-0002-2092-5145
authors.initials: S
authors.lastname: Balan
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Sundvold-Gjerstad
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Marseille Cedex 09, France.
authors.forename: Catharina
authors.initials: C
authors.lastname: Arnold-Schrauf
authors.affiliation: Centre for Immune Regulation, Department of Pathology, University of Oslo and Oslo University Hospital, 0027 Oslo, Norway; and.
authors.forename: Lisa
authors.identifier: 0000-0002-0769-619X
authors.initials: L
authors.lastname: Richter
authors.affiliation: Centre for Immune Regulation, Department of Pathology, University of Oslo and Oslo University Hospital, 0027 Oslo, Norway; and.
authors.forename: Espen S
authors.initials: ES
authors.lastname: Bækkevold
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Marseille Cedex 09, France.
authors.forename: Marc
authors.identifier: 0000-0002-6436-7966
authors.initials: M
authors.lastname: Dalod
authors.affiliation: K.G. Jebsen Centre for Influenza Vaccine Research, University of Oslo and Oslo University Hospital, 0450 Oslo, Norway; even.fossum@rr-research.no bjarne.bogen@medisin.uio.no.|Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital, 0027 Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.affiliation: K.G. Jebsen Centre for Influenza Vaccine Research, University of Oslo and Oslo University Hospital, 0450 Oslo, Norway; even.fossum@rr-research.no bjarne.bogen@medisin.uio.no.
authors.forename: Even
authors.initials: E
authors.lastname: Fossum
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004705:Endocytosis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D043562:Receptors, G-Protein-Coupled; C091671:XCR1 protein, human