Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C-type lectin receptor Langerin.
Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C-type lectin receptor Langerin.
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DOI：
10.1002/eji.202149670
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发表时间：
2022-11
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
--
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人类皮肤是首选的疫苗接种部位，因为它含有多种树突状细胞（DC）亚群，它们显示出识别病原体的不同C型凝集素受体（CLR）。抗原可以通过抗体或配体传递到CLR，以增强抗原特异性免疫反应。这一概念已在小鼠模型中建立，但对抗原原位递送到人皮肤DC的功能后果的详细见解尚不多见。在这项研究中，我们克隆并制备了一种结合EBV核抗原1 （EBNA1）的抗人Langerin抗体。我们证实了抗Langerin - EBNA1与Langerhans细胞（LC）的特异性结合。在与自体T细胞共培养之前，将这种新型LC - based疫苗与现有的抗DEC - 205 - EBNA1融合蛋白进行比较。再用EBNA1 -肽刺激后，我们检测到两种疫苗的IFN - γ -和TNF - α -阳性CD4+ T细胞水平升高。当我们将融合蛋白皮下注射到人皮肤外植体中时，通过T细胞产生DEC‐205诱导的细胞因子来迁移皮肤DC，而基于Langerin的疫苗却没有做到这一点。总之，我们证明了通过皮肤的抗体靶向方法是很有前途的疫苗接种策略，然而，需要进一步优化疫苗以诱导有效的免疫反应。抗原递送到皮肤树突状细胞可以通过靶向表达在朗格汉斯细胞和真皮树突状细胞上的Langerin或DEC‐205来实现。该研究表明，Langerin在体外可将蛋白质递送至Langerhans细胞，然而，在皮肤外植体模型中测试时，DEC‐205作为疫苗接种方法更有效。
Human skin is a preferred vaccination site as it harbors multiple dendritic cell (DC) subsets, which display distinct C‐type lectin receptors (CLR) that recognize pathogens. Antigens can be delivered to CLR by antibodies or ligands to boost antigen‐specific immune responses. This concept has been established in mouse models but detailed insights into the functional consequences of antigen delivery to human skin DC in situ are sparse. In this study, we cloned and produced an anti‐human Langerin antibody conjugated to the EBV nuclear antigen 1 (EBNA1). We confirmed specific binding of anti‐Langerin‐EBNA1 to Langerhans cells (LC). This novel LC‐based vaccine was then compared to an existing anti‐DEC‐205‐EBNA1 fusion protein by loading LC in epidermal cell suspensions before coculturing them with autologous T cells. After restimulation with EBNA1‐peptides, we detected elevated levels of IFN‐γ‐ and TNF‐α‐positive CD4+ T cells with both vaccines. When we injected the fusion proteins intradermally into human skin explants, emigrated skin DC targeted via DEC‐205‐induced cytokine production by T cells, whereas the Langerin‐based vaccine failed to do so. In summary, we demonstrate that antibody‐targeting approaches via the skin are promising vaccination strategies, however, further optimizations of vaccines are required to induce potent immune responses. Antigen delivery to skin dendritic cells can be achieved by targeting either Langerin or DEC‐205 expressed on Langerhans cells and dermal dendritic cells. This study demonstrates that Langerin delivers proteins to Langerhans cells in vitro, however, DEC‐205 was more potent as vaccination approach when tested in a skin explant model.
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DOI：
10.1038/jid.2009.343
发表时间：
2010-03
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
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DOI：
10.1084/jem.194.6.769
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Nussenzweig MC
影响因子：
15.3
作者：
Long, Heather M.;Chagoury, Odette L.;Rickinson, Alan B.
通讯作者：
Rickinson, Alan B.
影响因子：
100.3
作者：
Kastenmueller, Wolfgang;Kastenmueller, Kathrin;Seder, Robert A.
通讯作者：
Seder, Robert A.
癌症免疫疗法。树突状细胞疫苗增加了黑色素瘤新抗原特异性T细胞的广度和多样性。
DOI：
10.1126/science.aaa3828
发表时间：
2015-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carreno BM;Magrini V;Becker-Hapak M;Kaabinejadian S;Hundal J;Petti AA;Ly A;Lie WR;Hildebrand WH;Mardis ER;Linette GP
通讯作者：
Linette GP