Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules
Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules
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DOI：
10.1073/pnas.1809465115
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发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Boyle, Louise H.
中科院分区：
文献类型：
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作者：
Ilca, F. Tudor;Neerincx, Andreas;Boyle, Louise H.
MHC分子在细胞表面显示的肽库是由两个细胞内肽编辑器tapasin和TAPBPR塑造的。虽然无细胞检测在鉴定这两种蛋白质的功能方面非常有用，但我们探索了是否可以开发一个更生理的系统来评估TAPBPR介导的MHC I上的肽编辑。我们发现，靶向质膜的膜相关TAPBPR保留了其作为肽编辑器的功能，并有效地催化表面表达的MHC I分子上的肽交换。此外，我们发现，添加到完整细胞中的可溶性TAPBPR，仅由管腔结构域组成，也可以作为MHC I表面分子的有效肽编辑器。因此，我们已经建立了两个系统，其中tapbpr介导的MHC I类肽交换可以被询问。此外，我们可以使用质膜靶向和外源性可溶性TAPBPR在MHC I分子表面显示免疫原性肽，从而诱导T细胞受体参与、ifn - γ分泌和T细胞介导的靶细胞杀伤。因此，我们已经开发出一种有效的方法来绕过细胞的天然抗原递呈途径，并将选择的免疫原性肽加载到细胞上。我们的发现强调了TAPBPR在未来增加肿瘤免疫原性方面的潜在治疗用途。
The repertoire of peptides displayed at the cell surface by MHC molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-gamma secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future.