The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x.
Schistosoma mansoni soluble egg antigens (SEAs) are crucially involved in modulating the host immune response to infection by S. mansoni. We report that human dendritic cells bind SEAs through the C-type lectin dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN). Monoclonal antibodies against the carbohydrate antigens Lewisx (Lex) and GalNAcbeta1-4(Fucalpha1-3)GlcNAc (LDNF) inhibit binding of DC-SIGN to SEAs, suggesting that these glycan antigens may be critically involved in binding. In a solid-phase adhesion assay, DC-SIGN-Fc binds polyvalent neoglycoconjugates that contain the Lex antigen, whereas no binding was observed to Galbeta1-4GlcNAc, and binding to neoglycoconjugates containing only alpha-fucose or oligosaccharides with a terminal alpha1-2-linked fucose is low. These data indicate that binding of DC-SIGN to Lex antigen is fucose-dependent and that adjacent monosaccharides and/or the anomeric linkage of the fucose are important for binding activity. Previous studies have shown that DC-SIGN binds HIV gp120 that contains high-mannose-type N-glycans. Site-directed mutagenesis within the carbohydrate recognition domain (CRD) of DC-SIGN demonstrates that amino acids E324 and E347 are involved in binding to HIV gp120, Lex, and SEAs. By contrast, mutation of amino acid Val351 abrogates binding to SEAs and Lex but not HIV gp120. These data suggest that DC-SIGN recognizes these ligands through different (but overlapping) regions within its CRD. Our data imply that DC-SIGN not only is a pathogen receptor for HIV gp120 but may also function in pathogen recognition by interaction with the carbohydrate antigens Lex and possibly LDNF, which are found on important human pathogens, such as schistosomes and the bacterium Helicobacter pylori.
van Die
Irma
I
Department of Molecular Cell Biology, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. im.van_die.medchem@med.vu.nl
van Vliet
Sandra J
SJ
Nyame
A Kwame
AK
Cummings
Richard D
RD
Bank
Christine M C
CM
Appelmelk
Ben
B
Geijtenbeek
Teunis B H
TB
van Kooyk
Yvette
Y
D000595:Amino Acid Sequence; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D002236:Carbohydrate Conformation; D015815:Cell Adhesion Molecules / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology*; D016256:Lewis X Antigen / Q000276:immunology*; D008024:Ligands; D008969:Molecular Sequence Data; D010063:Ovum / Q000276:immunology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000947:Antigens, Helminth; D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D016256:Lewis X Antigen; D008024:Ligands; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin