Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKK[epsilon]- and CYLD-dependent Bcl3 activation

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 (TH 2) 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, IKK[straight epsilon] and CYLD are recruited to phosphorylated LSP1. IKK[straight epsilon] 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 TH 2-attracting chemokine expression, shifting TH differentiation from TH 1 to TH 2 polarization. Thus, DC-SIGN directs adaptive TH 2 immunity to fucose-expressing pathogens via an IKK[straight epsilon]-CYLD-dependent signalling pathway leading to Bcl3 activation, which might be targeted in vaccination strategies or to prevent aberrant inflammation and allergy.