Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity
Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity
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DOI：
10.1016/j.celrep.2023.112827
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发表时间：
2023-07
期刊：
影响因子：
8.8
通讯作者：
Yuan Chen;Georgina H Mason;D. O. Scourfield;Alexander Greenshields-Watson;T. Haigh;A. Sewell;H. Long;A. Gallimore;P. Rizkallah;B. MacLachlan;A. Godkin
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作者：
Yuan Chen;Georgina H Mason;D. O. Scourfield;Alexander Greenshields-Watson;T. Haigh;A. Sewell;H. Long;A. Gallimore;P. Rizkallah;B. MacLachlan;A. Godkin
CD4+T 细胞可识别严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的多种肽表位，这些表位有助于免疫记忆并限制 COVID-19 疾病。我们证明，在模型同种异型 HLA-DR1 的背景下，SARS-CoV-2 肽的免疫原性与其与 HLA 异二聚体的结合亲和力无关。通过分析六个表位（其中一些表位的结合亲和力非常低），我们解析了每个表位与 HLA-DR1 结合的 X 射线晶体结构。进一步的结构定义揭示了病毒变异突变对表位呈现的精确分子影响。 Omicron 通过两种不同的机制逃脱了对两个表位的祖先 SARS-CoV-2 免疫：(1) 面向 TCR 的表位位置发生突变，以及 (2) 单个氨基酸取代导致 HLA 结合槽内寄存器移位的机制，从而完全改变了肽-HLA 结构。这种 HLA-II 特异性免疫逃逸范例强调了 CD4+T 细胞记忆如何在肽-HLA-II 呈递水平上保持良好状态。
CD4+T cells recognize a broad range of peptide epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which contribute to immune memory and limit COVID-19 disease. We demonstrate that the immunogenicity of SARS-CoV-2 peptides, in the context of the model allotype HLA-DR1, does not correlate with their binding affinity to the HLA heterodimer. Analyzing six epitopes, some with very low binding affinity, we solve X-ray crystallographic structures of each bound to HLA-DR1. Further structural definitions reveal the precise molecular impact of viral variant mutations on epitope presentation. Omicron escaped ancestral SARS-CoV-2 immunity to two epitopes through two distinct mechanisms: (1) mutations to TCR-facing epitope positions and (2) a mechanism whereby a single amino acid substitution caused a register shift within the HLA binding groove, completely altering the peptide-HLA structure. This HLA-II-specific paradigm of immune escape highlights how CD4+T cell memory is finely poised at the level of peptide-HLA-II presentation.