title: Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-alpha production.
abstract: C-type lectin receptors (CLRs) fulfill multiple functions within the immune system by recognition of carbohydrate moieties on foreign or (altered) self-structures. CLRs on myeloid dendritic cells (DCs) have been well characterized as pattern-recognition receptors (PRRs) combining ligand internalization with complex signaling events. Much less is known about CLR expression and function in human plasmacytoid DCs (pDCs), the major type I interferon (IFN) producers. In this study, we demonstrate that, next to the CLR BDCA-2, human pDCs express DC immunoreceptor (DCIR), a CLR with putative immune-inhibitory function, but not dectin-1, mannose receptor, or DC-specific ICAM-3-grabbing nonintegrin. DCIR surface levels are reduced on pDC maturation after TLR9 triggering. Interestingly, DCIR triggering inhibits TLR9-induced IFN-alpha production while leaving up-regulation of costimulatory molecule expression unaffected. Furthermore, DCIR is readily internalized into pDCs after receptor triggering. We show that DCIR internalization is clathrin-dependent because it can be inhibited by hypertonic shock and dominant-negative dynamin. Importantly, antigens targeted to pDCs via DCIR are presented to T cells. These findings indicate that targeting DCIR on pDCs not only results in efficient antigen presentation but also affects TLR9-induced IFN-alpha production. Collectively, the data show that targeting of DCIR can modulate human pDC function and may be applied in disease prevention and treatment.
authors.affiliation: Department of Tumor Immunology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Friederike
authors.initials: F
authors.lastname: Meyer-Wentrup
authors.forename: Daniel
authors.initials: D
authors.lastname: Benitez-Ribas
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tacken
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D016466:CHO Cells; D002454:Cell Differentiation; D002460:Cell Line; D002966:Clathrin / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004705:Endocytosis; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis*; D037181:Lectins, C-Type / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: C423004:CLEC4A protein, human; D002966:Clathrin; D007370:Interferon Type I; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D051217:Toll-Like Receptor 9; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin