Cross-presentation through langerin and DC-SIGN targeting requires different formulations of glycan-modified antigens

• Published in: Journal of controlled release 2015-04, Vol.203, p.67-76
• Main Authors: Fehres, Cynthia M, Kalay, Hakan, Bruijns, Sven C M, Musaafir, Sara A M, Ambrosini, Martino, van Bloois, Louis, van Vliet, Sandra J, Storm, Gert, Garcia-Vallejo, Juan J, van Kooyk, Yvette
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigen Presentation; Antigens - chemistry; Antigens - immunology; Antigens, CD - immunology; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Carbohydrate Sequence; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Adhesion Molecules - immunology; Cross-Priming; Dendritic Cells - immunology; Drug Delivery Systems; Glycoconjugates - chemistry; Glycoconjugates - immunology; Glycosphingolipids - chemistry; Glycosphingolipids - immunology; Humans; Langerhans Cells - immunology; Lectins, C-Type - immunology; Liposomes - chemistry; Liposomes - immunology; Mannose-Binding Lectins - immunology; Molecular Sequence Data; Peptides - chemistry; Peptides - immunology; Polysaccharides - chemistry; Polysaccharides - immunology; Receptors, Cell Surface - immunology
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.01.040

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.