title: Vaccine molecules targeting Xcr1 on cross-presenting DCs induce protective CD8+ T-cell responses against influenza virus.
abstract: Targeting antigens to cross-presenting dendritic cells (DCs) is a promising method for enhancing CD8(+) T-cell responses. However, expression patterns of surface receptors often vary between species, making it difficult to relate observations in mice to other animals. Recent studies have indicated that the chemokine receptor Xcr1 is selectively expressed on cross-presenting murine CD8α(+) DCs, and that the expression is conserved on homologous DC subsets in humans (CD141(+) DCs), sheep (CD26(+) DCs), and macaques (CADM1(+) DCs). We therefore tested if targeting antigens to Xcr1 on cross-presenting DCs using antigen fused to Xcl1, the only known ligand for Xcr1, could enhance immune responses. Bivalent Xcl1 fused to model antigens specifically bound CD8α(+) DCs and increased proliferation of antigen-specific T cells. DNA vaccines encoding dimeric Xcl1-hemagglutinin (HA) fusion proteins induced cytotoxic CD8(+) T-cell responses, and mediated full protection against a lethal challenge with influenza A virus. In addition to enhanced CD8(+) T-cell responses, targeting of antigen to Xcr1 induced CD4(+) Th1 responses and highly selective production of IgG2a antibodies. In conclusion, targeting of dimeric fusion vaccine molecules to CD8α(+) DCs using Xcl1 represents a novel and promising method for induction of protective CD8(+) T-cell responses.
authors.affiliation: K.G. Jebsen Center for Influenza Vaccine Research, Institute of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Even
authors.initials: E
authors.lastname: Fossum
authors.forename: Gunnveig
authors.initials: G
authors.lastname: Grødeland
authors.forename: Dorothea
authors.initials: D
authors.lastname: Terhorst
authors.forename: Anders A
authors.initials: AA
authors.lastname: Tveita
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vikse
authors.forename: Siri
authors.initials: S
authors.lastname: Mjaaland
authors.forename: Sandrine
authors.initials: S
authors.lastname: Henri
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D049109:Cell Proliferation; D045142:Cross-Priming; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000096:biosynthesis*; D009980:Influenza A virus / Q000187:drug effects / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; C551408:XC chemokine receptor 1, mouse; C483468:hemagglutinin, human influenza A virus
keywords: CD8+ T-cell responses; Dendritic cells; Influenza; Vaccine; Xcr1