title: Epitope mapping on the dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) pathogen-attachment factor.
abstract: DC-SIGN (dendritic cell-specific ICAM-3-grabbing non-integrin) is a myeloid pathogen-attachment factor C-type lectin which recognizes mannose- and fucose-containing oligosaccharide ligands on clinically relevant pathogens. Intracellular signaling initiated upon ligand engagement of DC-SIGN interferes with TLR-initiated signals, and modulates the T cell activating and polarizing ability of antigen-presenting cells. The C-terminal carbohydrate-recognition domain (CRD) of DC-SIGN is preceded by a neck domain composed of eight 23-residue repeats which mediate molecule multimerization, and whose polymorphism correlates with altered susceptibility to SARS and HIV infection. Naturally occurring isoforms and chimaeric molecules, in combination with established recognition properties, were used to define seven structural and functional epitopes on DC-SIGN. Three epitopes mapped to the CRD, one of which is multimerization-dependent and only exposed on DC-SIGN monomers. Epitopes within the neck domain were conformation-independent and unaltered upon molecule multimerization, but were differentially affected by neck domain truncations. Although neck-specific antibodies exhibited lower function-blocking ability, they were more efficient at inducing molecule internalization. Moreover, crosslinking of the different epitopes resulted in distinct levels of microclustering on the cell surface. The identification of independent epitopes on the DC-SIGN molecule might facilitate the design of reagents that modulate the T cell activating and polarizing ability of DC-SIGN-expressing cells without preventing its antigen- and pathogen-recognition capacities.
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sierra-Filardi
authors.forename: Ana
authors.initials: A
authors.lastname: Estecha
authors.forename: Rafael
authors.initials: R
authors.lastname: Samaniego
authors.forename: Elena
authors.initials: E
authors.lastname: Fernández-Ruiz
authors.forename: María
authors.initials: M
authors.lastname: Colmenares
authors.forename: Paloma
authors.initials: P
authors.lastname: Sánchez-Mateos
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.forename: Angela
authors.initials: A
authors.lastname: Granelli-Piperno
authors.forename: Angel L
authors.initials: AL
authors.lastname: Corbí
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004705:Endocytosis / Q000276:immunology; D018604:Epitope Mapping; D005455:Fluorescent Antibody Technique; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry* / Q000276:immunology*; D009000:Monocytes / Q000166:cytology; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin