Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes
Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes
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DOI：
10.1038/mt.2008.122
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发表时间：
2008-08-01
影响因子：
12.4
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
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作者：
Nakamura, Takashi;Moriguchi, Rumiko;Harashima, Hideyoshi
近年来，细胞穿透肽(CPPs)作为一种通过主要组织相容性复合体I类(MHC-I)途径递呈的抗原递送工具备受关注。然而，CPPs从内吞体内逃逸效率低下，因此是抗原传递的瓶颈。在此之前，我们展示了在脂质体表面拓扑控制八精氨酸(R8)多肽对调节细胞摄取和细胞内转运，特别是内体逃逸的重要性。在这项研究中，我们假设通过控制R8修饰脂质体(R8-Lip)中的抗原在细胞内的转运，可以实现高效的MHC-I递呈。R8-Lip和阳离子脂质体的摄取机制被证明是通过树突状细胞的大吞噬作用。然而，激光共聚焦扫描显微镜(CLSM)显示，R8-Lip能够比阳离子脂质体释放更多的抗原到胞浆中。R8-Lip递送的抗原的加工是蛋白酶体依赖的，这与R8-Lip通过MHC-I选择性提呈抗原是一致的。根据抗原递呈分析，R8-Lip在较低剂量下可以显著高于pH敏感或阳离子脂质体中的可溶性卵白蛋白(OVA)或OVA。此外，R8-Lip在体内显示出有效的抗肿瘤作用。因此，R8-Lip是一种很有前途的MHC-I抗原提呈的新载体。
Recently, much attention has been paid to cell-penetrating peptides (CPPs) as an antigen-delivery tool for presentation through the major histocompatibility complex class I (MHC-I) pathway. However, escape of CPPs from the endosome is inefficient and therefore a bottleneck for antigen delivery. Previously, we showed the importance of topological control of octaarginine (R8) peptides on the liposome surface for regulating cellular uptake as well as intracellular trafficking, especially endosomal escape. In this study, we hypothesized that efficient MHC-I presentation could be achieved by controlled intracellular trafficking of antigen encapsulated in R8-modified liposomes (R8-Lip). The mechanism of uptake of both R8-Lip and cationic liposomes was shown to be by macropinocytosis in dendritic cells. However, confocal laser scanning microscopy (CLSM) revealed that R8-Lip are able to release significantly more antigen to the cytosol than are cationic liposomes. Processing of the antigens delivered by R8-Lip was shown to be proteasome-dependent, which is consistent with selective antigen presentation by R8-Lip via MHC-I. According to antigen-presentation analysis, R8-Lip can induce significantly higher MHC-I presentation at lower doses than either soluble ovalbumin ( OVA) or OVA in pH-sensitive or cationic liposomes. Moreover, R8-Lip showed an efficient antitumor effect in vivo. Therefore, R8-Lip is a promising new carrier for MHC-I-specific antigen presentation.