The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells

• Published in: Blood 2012-03, Vol.119 (10), p.2284-2292
• Main Authors: Schreibelt, Gerty, Klinkenberg, Lieke J.J., Cruz, Luis J., Tacken, Paul J., Tel, Jurjen, Kreutz, Martin, Adema, Gosse J., Brown, Gordon D., Figdor, Carl G., de Vries, I. Jolanda M.
• Format: Article
• Language: English
• Subjects: Antigen Presentation - immunology; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Surface - immunology; Antigens, Surface - metabolism; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; Cross-Priming - immunology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Endocytosis - immunology; Flow Cytometry; Hematologic and hematopoietic diseases; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; Humans; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; Medical sciences; Minor Histocompatibility Antigens; Myeloid Cells - immunology; Myeloid Cells - metabolism; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Receptors, Mitogen - immunology; Receptors, Mitogen - metabolism; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-08-373944

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.