DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN.
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 Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) 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 Lewis(X) 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-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). 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.
Meyer
Sandra
S
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University Giessen, Germany.
van Liempt
Ellis
E
Imberty
Anne
A
van Kooyk
Yvette
Y
Geyer
Hildegard
H
Geyer
Rudolf
R
van Die
Irma
I
D000818:Animals; D001665:Binding Sites; D002240:Carbohydrate Sequence; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D007983:Lewis Blood Group Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000276:immunology / Q000378:metabolism*; D013045:Species Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D006017:Glycolipids; D037181:Lectins, C-Type; D007983:Lewis Blood Group Antigens; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C094162:Lewis Y antigen