DC-SIGN mediates binding of dendritic cells to authentic pseudo-Lewis Y glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN

Abstract

During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galβ1- 4(Fucα1-3) GlcNAc (LewisX) and Fucα1-3Galβ1-4(Fucα1-3)GlcNAc (pseudo-LewisY) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to LewisX provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis Y to DC-SIGN is not directly compatible with the model described. To fit pseudo-LewisY into the model, the orientation of the side chain of Phe313 in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe313 with the hydrophobic side of the galactose-linked fucose of pseudo-LewisY. We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.