title: Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation.
abstract: Carbohydrate-specific signalling through DC-SIGN provides dendritic cells with plasticity to tailor immunity to the nature of invading microbes. Here we demonstrate that recognition of fucose-expressing extracellular pathogens like Schistosoma mansoni and Helicobacter pylori by DC-SIGN favors T helper cell type-2 (TH2) responses via activation of atypical NF-κB family member Bcl3. Crosstalk between TLR and DC-SIGN signalling results in TLR-induced MK2-mediated phosphorylation of LSP1, associated with DC-SIGN, upon fucose binding. Subsequently, IKKε and CYLD are recruited to phosphorylated LSP1. IKKε activation is pivotal for suppression of CYLD deubiquitinase activity and subsequent nuclear translocation of ubiquitinated Bcl3. Bcl3 activation represses TLR-induced proinflammatory cytokine expression, while enhancing interleukin-10 (IL-10) and TH2-attracting chemokine expression, shifting TH differentiation from TH1 to TH2 polarization. Thus, DC-SIGN directs adaptive TH2 immunity to fucose-expressing pathogens via an IKKε-CYLD-dependent signalling pathway leading to Bcl3 activation, which might be targeted in vaccination strategies or to prevent aberrant inflammation and allergy.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Kaptein
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Brigitte A
authors.initials: BA
authors.lastname: Wevers
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Annelies W
authors.initials: AW
authors.lastname: Mesman
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005643:Fucose / Q000378:metabolism*; D016480:Helicobacter pylori / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D016256:Lewis X Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; D015815:Cell Adhesion Molecules; D018925:Chemokines; D000074749:Deubiquitinating Enzyme CYLD; D005643:Fucose; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D016256:Lewis X Antigen; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D016328:NF-kappa B; D010768:Phosphoserine; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C000631344:BCL3 protein, human; C489183:LSP1 protein, human; C409984:CYLD protein, human