Department of Molecular Cell Biology and Immunology, VUmc, Amsterdam, The Netherlands.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
J Control Release. 2015 Apr 10;203:67-76. doi: 10.1016/j.jconrel.2015.01.040. Epub 2015 Feb 2.
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.
树突状细胞（DCs）和朗格汉斯细胞（LCs）是专业的抗原呈递细胞（APCs），能够引发体液和细胞免疫应答。针对树突状细胞或 LC 特异性受体的抗原靶向递呈可增强疫苗的疗效。在这项研究中，我们比较了糖基抗原靶向人类树突状细胞特异性 C 型凝集素受体（CLR）DC-SIGN 和 LC 特异性 CLR langerin 的效率。由于 DC-SIGN 和 langerin 能够识别二岩藻糖基化寡糖 Lewis Y（Le(Y)），我们制备了带有该糖基表位的糖基化结合物，以允许靶向两种凝集素。带有大约 200nm 直径的 Le(Y)修饰的脂质体被 DC-SIGN(+)DCs 显著内吞，并介导对 CD4(+)和 CD8(+)T 细胞的有效抗原呈递。令人惊讶的是，尽管 langerin 与 Le(Y)修饰的脂质体结合，但暴露于 Le(Y)修饰的脂质体的 LCs 不能内吞脂质体，也不能介导抗原呈递给 T 细胞。然而，当抗原通过 langerin 用 Le(Y)修饰的合成长肽递呈时，LCs 介导了增强的交叉呈递。相比之下，Le(Y)修饰的合成长肽被 DC-SIGN 识别，但不会触发抗原内化或抗原交叉呈递。这些数据表明，langerin 和 DC-SIGN 对抗原摄取有不同的大小要求。尽管使用聚糖仍然是设计针对多个 CLR 的抗癌疫苗的一个有趣选择，但需要考虑分子大小和构象等方面。
