Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway
Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway
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DOI：
10.4049/jimmunol.179.3.1803
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Sato, Noriyuki
中科院分区：
文献类型：
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作者：
Kurotaki, Takehiro;Tamura, Yasuaki;Sato, Noriyuki
众所周知，热休克蛋白（HSP）-肽复合物在预防性和治疗性免疫方案中引发抗肿瘤反应。已证明 gp96 和 Hsp70 等 HSP 会被 APC 进行受体介导的摄取，随后将 HSP 相关肽呈现为 APC 上的 MHC I 类分子，从而促进有效的交叉呈递。相反，尽管 Hsp90 在细胞质中的 HSP 中大量表达，但 Hsp90 在交叉呈递中的作用仍然未知。我们在此表明，外源性 Hsp90-肽复合物可以进入 MHC I 类呈递途径，并引起骨髓源性树突状细胞的交叉呈递。有趣的是，这种呈现不依赖于 TAP，并且遵循氯喹、亮肽素敏感以及组织蛋白酶 S 依赖性内体途径。此外，我们还发现 Hsp90 陪伴的前体肽被加工并转移到内体区室中的 MHC I 类分子上。此外，我们证明用Hsp90-肽复合物进行免疫可诱导Ag特异性CD8(+) T细胞反应和体内强抗肿瘤免疫。这些发现对于基于 T 细胞的癌症免疫疗法的设计具有重要意义。
It is well-established that heat shock proteins (HSPs)-peptides complexes elicit antitumor responses in prophylactic and therapeutic immunization protocols. HSPs such as gp96 and Hsp70 have been demonstrated to undergo receptor-mediated uptake by APCs vvith subsequent representation of the HSP-associated peptides to MHC class I molecules on APCs, facilitating efficient cross-presentation. On the contrary, despite its abundant expression among HSPs in the cytosol, the role of Hsp90 for the cross-presentation remains unknown. We show here that exogenous Hsp90-peptide complexes can gain access to the MHC class I presentation pathway and cause cross-presentation by bone marrow-derived dendritic cells. Interestingly, this presentation is TAP independent, and followed chloroquine, leupeptin-sensitive, as well as cathepsin S-dependent endosomal pathways. In addition, we show that Hsp90-chaperoned precursor peptides are processed and transferred onto MHC class I molecules in the endosomal compartment. Furthermore, we demonstrate that immunization with Hsp90-peptide complexes induce Ag-specific CD8(+) T cell responses and strong antitumor immunity in vivo. These findings have significant implications for the design of T cell-based cancer immunotherapy.