title: Cross-presentation through langerin and DC-SIGN targeting requires different formulations of glycan-modified antigens.
abstract: Dendritic cells (DCs) and Langerhans cells (LC) are professional antigen presenting cells (APCs) that initiate humoral and cellular immune responses. Targeted delivery of antigen towards DC- or LC-specific receptors enhances vaccine efficacy. In this study, we compared the efficiency of glycan-based antigen targeting to both the human DC-specific C-type lectin receptor (CLR) DC-SIGN and the LC-specific CLR langerin. Since DC-SIGN and langerin are able to recognize the difucosylated oligosaccharide Lewis Y (Le(Y)), we prepared neoglycoconjugates bearing this glycan epitope to allow targeting of both lectins. Le(Y)-modified liposomes, with an approximate diameter of 200nm, were significantly endocytosed by DC-SIGN(+) DCs and mediated efficient antigen presentation to CD4(+) and CD8(+) T cells. Surprisingly, although langerin bound to Le(Y)-modified liposomes, LCs exposed to Le(Y)-modified liposomes could not endocytose liposomes nor mediate antigen presentation to T cells. However, LCs mediated an enhanced cross-presentation when antigen was delivered through langerin using Le(Y)-modified synthetic long peptides. In contrast, Le(Y)-modified synthetic long peptides were recognized by DC-SIGN, but did not trigger antigen internalization nor antigen cross-presentation. These data demonstrate that langerin and DC-SIGN have different size requirements for antigen uptake. Although using glycans remains an interesting option in the design of anti-cancer vaccines targeting multiple CLRs, aspects such as molecule size and conformation need to be taken in consideration.
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Cynthia M
authors: CM
authors: Fehres
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Hakan
authors: H
authors: Kalay
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Sven C M
authors: SC
authors: Bruijns
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Sara A M
authors: SA
authors: Musaafir
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Martino
authors: M
authors: Ambrosini
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors: Louis
authors: L
authors: van Bloois
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Sandra J
authors: SJ
authors: van Vliet
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands; MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors: Gert
authors: G
authors: Storm
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
authors: Juan J
authors: JJ
authors: Garcia-Vallejo
authors: Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands. Electronic address: y.vankooyk@vumc.nl.
authors: Yvette
authors: Y
authors: van Kooyk
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D002240:Carbohydrate Sequence; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems; D006001:Glycoconjugates / Q000737:chemistry / Q000276:immunology*; D006028:Glycosphingolipids / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008081:Liposomes / Q000737:chemistry / Q000276:immunology*; D037241:Mannose-Binding Lectins / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011134:Polysaccharides / Q000737:chemistry / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000941:Antigens; D015703:Antigens, CD; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D006001:Glycoconjugates; D006028:Glycosphingolipids; D037181:Lectins, C-Type; D008081:Liposomes; D037241:Mannose-Binding Lectins; D010455:Peptides; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C121916:CD207 protein, human; C055089:Y glycolipid
keywords: Anti-tumor vaccination; DC-SIGN; Glycans; Human dendritic cells; Langerin; Liposomes