title: Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells.
abstract: The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3(+) (CD141(+)) subset DCs may be particularly effective in DC vaccination trials. BDCA-3(+) DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3(+) DCs in elicitation of HCMV-specific CD8(+) T-cell clones. We show that Fcgamma-receptor (FcγR) antigen targeting facilitates antigen cross-presentation in several DC subsets, including BDCA-3(+) DCs. FcγR antigen targeting stimulates antigen uptake by BDCA-1(+) rather than BDCA-3(+) DCs. Conversely, BDCA-3(+) DCs and not BDCA-1(+) DCs show improved cross-presentation by FcγR targeting, as measured by induced release of IFNγ and TNF by antigen-specific CD8(+) T cells. FcγR-facilitated cross-presentation requires antigen processing in both an acidic endosomal compartment and by the proteasome, and did not induce substantial DC maturation. FcγRII is the most abundantly expressed FcγR on both BDCA-1(+) and BDCA-3(+) DCs. Furthermore we show that BDCA-3(+) DCs express relatively more stimulatory FcγRIIa than inhibitory FcγRIIb in comparison with BDCA-1(+) DCs. These studies support the exploration of FcγR antigen targeting to BDCA-3(+) DCs for human vaccination purposes.
authors.affiliation: Departments of Pediatric Immunology, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Utrecht, The Netherlands.
authors.forename: Thijs W H
authors.initials: TW
authors.lastname: Flinsenberg
authors.forename: Ewoud B
authors.initials: EB
authors.lastname: Compeer
authors.forename: Dan
authors.initials: D
authors.lastname: Koning
authors.forename: Mark
authors.initials: M
authors.lastname: Klein
authors.forename: Femke J
authors.initials: FJ
authors.lastname: Amelung
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects / Q000502:physiology; D000954:Antigens, Surface / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D001769:Blood / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000494:pharmacology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000502:physiology; D018180:Thrombomodulin; D014763:Viral Matrix Proteins / Q000276:immunology / Q000494:pharmacology
chemical_list: D000954:Antigens, Surface; D000956:Antigens, Viral; D010750:Phosphoproteins; D017452:Receptors, IgG; C546931:THBD protein, human; D018180:Thrombomodulin; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa