title: DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production.
abstract: C-type lectin receptors (CLRs) expressed on APCs play a pivotal role in the immune system as pattern-recognition and antigen-uptake receptors. In addition, they may signal directly, leading to cytokine production and immune modulation. To this end, some CLRs, like dectin-1 and dendritic cell immunoreceptor (DCIR), contain intracellular ITIMs or ITAMs. In this study, we explored expression and function of the ITIM-containing CLR DCIR on professional APCs. DCIR is expressed on immature and mature monocyte-derived DCs (moDC) but also on monocytes, macrophages, B cells, and freshly isolated myeloid and plasmacytoid DCs. We show that endogenous DCIR is internalized efficiently into human moDC after triggering with DCIR-specific mAb. DCIR internalization is clathrin-dependent and leads to its localization in the endo-/lysosomal compartment, including lysosome-associated membrane protein-1+ lysosomes. DCIR triggering affected neither TLR4- nor TLR8-mediated CD80 and CD86 up-regulation. Interestingly, it did inhibit TLR8-mediated IL-12 and TNF-alpha production significantly, and TLR2-, TLR3-, or TLR4-induced cytokine production was not affected. Collectively, the data presented characterize DCIR as an APC receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. These data provide further support to the concept of CLR/TLR cross-talk in modulating immune responses.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Friederike
authors.initials: F
authors.lastname: Meyer-Wentrup
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cambi
authors.forename: Ben
authors.initials: B
authors.lastname: Joosten
authors.forename: Maaike W
authors.initials: MW
authors.lastname: Looman
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D037181:Lectins, C-Type / Q000378:metabolism* / Q000502:physiology; D008247:Lysosomes; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D020239:Receptor Cross-Talk / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism* / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: C423004:CLEC4A protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12