A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands
A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands
复制标题
DOI：
10.1126/sciimmunol.aar3947
复制
发表时间：
2018-10-01
影响因子：
24.8
通讯作者：
Purcell, Anthony W.
中科院分区：
文献类型：
--
作者：
Faridi, Pouya;Li, Chen;Purcell, Anthony W.
一类人白细胞抗原（HLA）所显示的肽的多样性在T细胞免疫中起着至关重要的作用。肽库通过各种翻译后修饰得到扩展，包括抗原不同区域的肽片段的蛋白酶体剪接，以形成非基因组模板顺式剪接序列。以前，有人认为免疫肽穹窿的一部分构成了这种顺式剪接肽；然而，由于计算的限制，还无法评估反式剪接肽（即不同抗原肽段的融合）是否也被HLA分子结合和呈递，如果是，比例是多少。在这里，我们开发并应用了一种生物信息学工作流程，并证明了反式剪接肽是由hla - 1呈现的，它们的丰度挑战了目前预测顺式剪接是最可能结果的蛋白酶体剪接模型。这些反式剪接肽显示出典型的hla结合序列特征，并且经常被鉴定为与许多不同的HLA-A和HLA-B同种异型结合的顺式剪接肽。结构分析表明，剪接肽之间的连接高度暴露于溶剂，可能参与T细胞受体的相互作用。这些结果突出了免疫肽穹窿意想不到的多样性，对自身免疫、疫苗设计和免疫治疗具有重要意义。
The diversity of peptides displayed by class I human leukocyte antigen (HLA) plays an essential role in T cell immunity. The peptide repertoire is extended by various posttranslational modifications, including proteasomal splicing of peptide fragments from distinct regions of an antigen to form nongenomically templated cis-spliced sequences. Previously, it has been suggested that a fraction of the immunopeptidome constitutes such cis-spliced peptides; however, because of computational limitations, it has not been possible to assess whether trans-spliced peptides (i.e., the fusion of peptide segments from distinct antigens) are also bound and presented by HLA molecules, and if so, in what proportion. Here, we have developed and applied a bioinformatic workflow and demonstrated that trans-spliced peptides are presented by HLA-I, and their abundance challenges current models of proteasomal splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA-binding sequence features and are as frequently identified as cis-spliced peptides found bound to a number of different HLA-A and HLA-B allotypes. Structural analysis reveals that the junction between spliced peptides is highly solvent exposed and likely to participate in T cell receptor interactions. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design, and immunotherapy.