Antibodies and carbohydrate ligands binding to DC-SIGN differentially modulate receptor trafficking.
DCs are regarded as key APCs that initiate humoral and cellular immune responses. Consequently, targeted delivery of Ag toward DC-specific receptors enhances vaccine efficacy. DC-SIGN is a C-type lectin receptor that facilitates DC-specific delivery of Ag. This is accomplished by conjugating Ag to receptor-specific Ab or carbohydrate ligands that bind to its carbohydrate recognition domain. Here, we investigated the fate of DC-SIGN following receptor triggering with Ab. Both whole and single-chain Ab induced rapid internalization of about half of the surface receptor molecules. Biochemical studies showed that about half of the receptor molecules were still intracellular after 3 h, while minimal or no resurfacing of internalized or newly synthesized unbound DC-SIGN molecules was observed. Prolonged exposure of DCs to DC-SIGN Ab, but not carbohydrate ligands, resulted in reduced receptor expression levels, which lasted up to 2 days following removal of the Ab. In addition, exposure to DC-SIGN Ab reduced the ability of the receptor to internalize. Consequently, DC-SIGN showed a poor ability to accumulate targeting Abs within DCs. Vaccine efficacy may therefore be enhanced by strategies increasing the amount of Ag entering via a single receptor molecule, such as the use of targeting moieties allowing DC-SIGN recycling or Ab-coated vaccine carriers.
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Paul J
PJ
Tacken
Menno
M
Ter Huurne
Ruurd
R
Torensma
Carl G
CG
Figdor
D000906:Antibodies / Q000276:immunology / Q000378:metabolism*; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism*; D002241:Carbohydrates / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014612:Vaccines / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000906:Antibodies; D000941:Antigens; D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008024:Ligands; D011956:Receptors, Cell Surface; D014612:Vaccines; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin