Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation
Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation
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DOI：
10.4049/jimmunol.176.2.1053
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发表时间：
2006-01-15
影响因子：
4.4
通讯作者：
Van den Eynde, BJ
中科院分区：
文献类型：
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作者：
Chapiro, J;Claverol, S;Van den Eynde, BJ
免疫蛋白酶体 (IP) 通常被认为有利于 MHC I 类分子呈递的抗原肽的产生，主要是因为其在疏水残基后具有较高的裂解活性，称为胰凝乳蛋白酶样活性。然而，已经发现一些肽可以通过标准蛋白酶体更好地产生。尚未描述这种差异处理的机制。通过研究临床感兴趣的三种肿瘤抗原肽的加工，我们证明它们的差异加工主要是由于两种蛋白酶体类型的内部切割效率的差异造成的。肽 gp100(209-217) (ITDQVPSFV) 和肽酪氨酸酶 (369-377) (YMDGTMSQV) 会被 IP 破坏，并在内部疏水残基后裂解。相反，肽 MAGE-C2(336-344) (ALKDVEERV) 在酸性残基后被标准蛋白酶体通过内部裂解破坏，这与其较高的酸后活性一致。这些结果表明，由于其较高的胰凝乳蛋白酶样活性，IP 可能会破坏一些抗原肽，而不是有利于其产生。他们还表明，两种蛋白酶体类型产生的肽组的差异比预期更大。考虑到成熟树突状细胞主要含有 IP，我们的结果对免疫治疗策略的设计具有重要意义。
The immunoproteasome (IP) is usually viewed as favoring the production of antigenic peptides presented by MHC class I molecules, mainly because of its higher cleavage activity after hydrophobic residues, referred to as the chymotrypsin-like activity. However, some peptides have been found to be better produced by the standard proteasome. The mechanism of this differential processing has not been described. By studying the processing of three tumor antigenic peptides of clinical interest, we demonstrate that their differential processing mainly results from differences in the efficiency of internal cleavages by the two proteasome types. Peptide gp100(209-217) (ITDQVPSFV) and peptide tyrosinase(369-377) (YMDGTMSQV) are destroyed by the IP, which cleaves after an internal hydrophobic residue. Conversely, peptide MAGE-C2(336-344) (ALKDVEERV) is destroyed by the standard proteasome by internal cleavage after an acidic residue, in line with its higher postacidic activity. These results indicate that the IP may destroy some antigenic peptides due to its higher chymotrypsin-like activity, rather than favor their production. They also suggest that the sets of peptides produced by the two proteasome types differ more than expected. Considering that mature dendritic cells mainly contain IPs, our results have implications for the design of immunotherapy strategies.