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

Gerty Schreibelt, Lieke J J Klinkenberg, Luis J Cruz, Paul J Tacken, Jurjen Tel, Martin Kreutz, Gosse J Adema, Gordon D Brown, Carl G Figdor, I Jolanda M de Vries

Research output: Contribution to journalArticle

130 Citations (Scopus)

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 anti-tumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3+ mDCs, which represent less than 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 Toll-like receptor-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.
Original languageEnglish
Pages (from-to)2284-2292
Number of pages9
JournalBlood
Volume119
Issue number10
Early online date10 Jan 2012
DOIs
Publication statusPublished - Mar 2012

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Cross-Priming
C-Type Lectins
Myeloid Cells
Dendritic Cells
Blood
Antigens
T-cells
Antibodies
T-Lymphocytes
Toll-Like Receptors
Histocompatibility Antigens Class II
Antigen Presentation
Tumors
Immunity
Melanoma
Leukocytes
Vaccines
Cytokines
Molecules
Neoplasms

Cite this

Schreibelt, G., Klinkenberg, L. J. J., Cruz, L. J., Tacken, P. J., Tel, J., Kreutz, M., ... de Vries, I. J. M. (2012). The C type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood, 119(10), 2284-2292. https://doi.org/10.1182/blood-2011-08-373944

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

In: Blood, Vol. 119, No. 10, 03.2012, p. 2284-2292.

Research output: Contribution to journalArticle

Schreibelt, G, Klinkenberg, LJJ, Cruz, LJ, Tacken, PJ, Tel, J, Kreutz, M, Adema, GJ, Brown, GD, Figdor, CG & de Vries, IJM 2012, 'The C type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells', Blood, vol. 119, no. 10, pp. 2284-2292. https://doi.org/10.1182/blood-2011-08-373944
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. / The C type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. In: Blood. 2012 ; Vol. 119, No. 10. pp. 2284-2292.
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AB - 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 anti-tumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3+ mDCs, which represent less than 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 Toll-like receptor-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.

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