title: The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells.
abstract: CLEC9A is a recently discovered C-type lectin receptor involved in sensing necrotic cells. In humans, this receptor is selectively expressed by BDCA3(+) myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8(+) DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8(+) DCs to both CD4(+) and CD8(+) T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3(+) mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3(+) mDCs and that cell surface expression is lost after TLR-mediated maturation. CLEC9A triggering via antibody binding rapidly induces receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3(+) mDCs are presented by both MHC class I (cross-presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Gerty
authors.initials: G
authors.lastname: Schreibelt
authors.forename: Lieke J J
authors.initials: LJ
authors.lastname: Klinkenberg
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Cruz
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tacken
authors.forename: Jurjen
authors.initials: J
authors.lastname: Tel
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutz
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D011975:Receptors, Mitogen / Q000276:immunology* / Q000378:metabolism; D018180:Thrombomodulin; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; C530206:CLEC9a protein, human; C093569:DEC-205 receptor; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; C546931:THBD protein, human; D018180:Thrombomodulin; D051193:Toll-Like Receptors