Induction of Endoplasmic Reticulum-Endosome Fusion for Antigen Cross-Presentation Induced by Poly (γ-Glutamic Acid) Nanoparticles
Induction of Endoplasmic Reticulum-Endosome Fusion for Antigen Cross-Presentation Induced by Poly (γ-Glutamic Acid) Nanoparticles
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DOI：
10.4049/jimmunol.1001093
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发表时间：
2011-12-15
影响因子：
4.4
通讯作者：
Nakagawa, Shinsaku
中科院分区：
文献类型：
--
作者：
Mukai, Yohei;Yoshinaga, Tomoyo;Nakagawa, Shinsaku
我们以前报道，聚（γ-谷氨酸）为基础的纳米粒子（γ-PGA NPs）是很好的疫苗载体诱导有效的交叉呈递在树突状细胞，从而产生强大的抗肿瘤免疫在体内。分析γ-PGA纳米粒诱导交叉呈递的机制将有助于设计新型疫苗载体。在这项研究中，我们显示了一种细胞内的机制，有效的交叉介绍诱导的OVA负载的γ-PGA纳米粒子。γ-PGA纳米颗粒诱导的交叉呈递依赖于细胞质蛋白酶体和TAP，类似于内源性Ag的经典MHC I类呈递途径。通过共聚焦激光扫描显微镜分析的细胞内行为显示，封装的OVA和γ-PGA在2小时内积聚在内质网（ER）和内体区室。同时，电子显微镜分析清楚地表明，细胞内的γ-PGA纳米颗粒和封装的Au纳米颗粒被包裹在内体样囊泡中，而不是在ER中。这些发现强烈表明γ-PGA NP增强ER-内体融合以用于交叉呈递。此外，ER易位子sec 61的抑制显著降低了γ-PGA NP/OVA介导的交叉呈递效率，表明sec 61对于将Ag从融合的ER-内体转运到细胞质是重要的。这些发现意味着ER-内体复合物是包封在γ-PGA NP中的Ag的有效交叉呈递的关键。免疫学杂志，2011，187：6249-6255。
We previously reported that poly (gamma-glutamic acid)-based nanoparticles (gamma-PGA NPs) are excellent vaccine carriers for inducing efficient cross-presentation in dendritic cells, thereby producing strong antitumor immunity in vivo. Analyzing the mechanism of cross-presentation induced by gamma-PGA NPs will be useful toward designing novel vaccine carriers. In this study, we show an intracellular mechanism of efficient cross-presentation induced by OVA-loaded gamma-PGA NPs. Cross-presentation induced by gamma-PGA NPs depended on cytoplasmic proteasomes and TAP, similar to the classical MHC class I presentation pathway for endogenous Ags. Intracellular behavior analyzed by confocal laser scanning microscopy revealed that encapsulated OVA and gamma-PGA accumulated in both the endoplasmic reticulum (ER) and endosome compartments within 2 h. At the same time, electron microscopy analysis clearly showed that intracellular gamma-PGA NPs and encapsulated Au NPs were enveloped in endosome-like vesicles, not in the ER. These findings strongly suggest that gamma-PGA NPs enhance ER-endosome fusion for cross-presentation. Moreover, inhibition of ER translocon sec61 significantly decreased the gamma-PGA NP/OVA-mediated cross-presentation efficiency, indicating that sec61 is important for transporting Ags from the fused ER-endosome to the cytoplasm. These findings imply that the ER-endosome complex is key for the efficient cross-presentation of Ags encapsulated in gamma-PGA NPs. The Journal of Immunology, 2011, 187: 6249-6255.