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

TY - JOUR

T1 - Cross-presentation through langerin and DC-SIGN targeting requires different formulation of glycan-modified antigens

AU - Fehres, Cynthia M.

AU - Kalay, Hakan

AU - Bruijns, Sven C.M.

AU - Musaafir, Sara A.M.

AU - Ambrosini, Martino

AU - van Bloois, Louis

AU - van Vliet, Sandra J.

AU - Storm, Gerrit

AU - Garcia-Vallejo, Juan J.

AU - van Kooyk, Yvette

PY - 2015

Y1 - 2015

N2 - 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 (LeY), we prepared neoglycoconjugates bearing this glycan epitope to allow targeting of both lectins. LeY-modified liposomes, with an approximate diameter of 200 nm, were significantly endocytosed by DC-SIGN+ DCs and mediated efficient antigen presentation to CD4+ and CD8+ T cells. Surprisingly, although langerin bound to LeY-modified liposomes, LCs exposed to LeY-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 LeY-modified synthetic long peptides. In contrast, LeY-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.

AB - 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 (LeY), we prepared neoglycoconjugates bearing this glycan epitope to allow targeting of both lectins. LeY-modified liposomes, with an approximate diameter of 200 nm, were significantly endocytosed by DC-SIGN+ DCs and mediated efficient antigen presentation to CD4+ and CD8+ T cells. Surprisingly, although langerin bound to LeY-modified liposomes, LCs exposed to LeY-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 LeY-modified synthetic long peptides. In contrast, LeY-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.

KW - METIS-315205

KW - IR-99647

U2 - 10.1016/j.jconrel.2015.01.040

DO - 10.1016/j.jconrel.2015.01.040

M3 - Article

VL - 203

SP - 67

EP - 76

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

ER -