Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides
Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides
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DOI：
10.1074/jbc.m114.607028
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发表时间：
2015-01-30
影响因子：
4.8
通讯作者：
van Veelen, Peter A.
中科院分区：
文献类型：
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作者：
Hassan, Chopie;Chabrol, Eric;van Veelen, Peter A.
背景：长表位对 T 细胞免疫的影响仍不清楚。结果：我们鉴定并表征了仅限于 HLA-A*02:01 的 15 聚体表位。结论：除了 HLA-B 家族之外，HLA-A*02:01 还可以结合代表 CD8(+) T 细胞新抗原靶标的长表位。意义：仅限于 HLA-A*02:01 的 15 聚体表位的表征扩展了我们对 HLA-配体的认识。人类白细胞抗原 (HLA) I 类分子通常呈现长度为 8 至 11 个氨基酸 (aa) 的肽 (p)。尽管已经报道了越来越多的长肽（>11 个氨基酸）的例子，这些肽主要由 HLA-B 等位基因呈现。在这里，除了 HLA-B*0702 和 HLA-B*4402 限制性长肽（>11 个氨基酸）外，我们还描述了 B 细胞配体组产生的 HLA-A*02:01 限制性肽。我们分析了 HLA-A*02:01 呈递的许多 15 聚体肽，并通过 HLA 折叠和热稳定性测定证实了 pHLA-I 的形成。令人惊讶的是，与 HLA-A*02:01 复合的 15 聚体表位的结合亲和力和稳定性与对规范长度（8 至 11 个氨基酸）HLA-A*02:01 限制性肽观察到的值相当。我们解析了与 HLA-A*02:01 复合的两个 15 聚体表位的结构，其中肽采用了独特的超级凸出构象。此外，我们证明 T 细胞可以识别 HLA-A*02:01 背景下的 15 聚体肽，表明这些 15 聚体肽代表免疫原性配体。总的来说，我们的数据扩展了我们对 HLA-I 中较长表位的理解，强调它们不仅限于 HLA-B 家族，还可以结合普遍存在的 HLA-A*02:01 分子，并在 T 细胞免疫中发挥重要作用。
Background: The impact of long epitopes on T-cell immunity remains unclear. Results: We identified and characterized 15-mer epitopes restricted to HLA-A*02:01. Conclusion: HLA-A*02:01, in addition to the HLA-B family, can bind long epitopes that represent new antigenic targets for CD8(+) T-cells. Significance: The characterization of 15-mer epitopes restricted to HLA-A*02:01 expands our knowledge of the HLA-ligandome.Human leukocyte antigen (HLA) class I molecules generally present peptides (p) of 8 to 11 amino acids (aa) in length. Although an increasing number of examples with lengthy (>11 aa) peptides, presented mostly by HLA-B alleles, have been reported. Here we characterize HLA-A*02:01 restricted, in addition to the HLA-B*0702 and HLA-B*4402 restricted, lengthy peptides (>11 aa) arising from the B-cell ligandome. We analyzed a number of 15-mer peptides presented by HLA-A*02:01, and confirmed pHLA-I formation by HLA folding and thermal stability assays. Surprisingly the binding affinity and stability of the 15-mer epitopes in complex with HLA-A*02:01 were comparable with the values observed for canonical length (8 to 11 aa) HLA-A*02:01-restricted peptides. We solved the structures of two 15-mer epitopes in complex with HLA-A*02:01, within which the peptides adopted distinct super-bulged conformations. Moreover, we demonstrate that T-cells can recognize the 15-mer peptides in the context of HLA-A*02:01, indicating that these 15-mer peptides represent immunogenic ligands. Collectively, our data expand our understanding of longer epitopes in the context of HLA-I, highlighting that they are not limited to the HLA-B family, but can bind the ubiquitous HLA-A*02:01 molecule, and play an important role in T-cell immunity.