分析 SARS-CoV-2 HLA-I 肽组揭示了来自框架外 ORFs 的 T 细胞表位。

Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs.

机构信息

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

出版信息

Cell. 2021 Jul 22;184(15):3962-3980.e17. doi: 10.1016/j.cell.2021.05.046. Epub 2021 Jun 3.

DOI:10.1016/j.cell.2021.05.046

PMID:34171305

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8173604/

Abstract

T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.

摘要

T 细胞介导的免疫在控制 SARS-CoV-2 感染方面发挥着重要作用，但关于人类白细胞抗原 I 类（HLA-I）上天然加工和呈递的病毒表位的文库仍未被描述。在这里，我们使用质谱法报道了两种细胞系在感染后不同时间点 SARS-CoV-2 的首个 HLA-I 免疫肽组。我们发现 HLA-I 肽不仅来自经典的开放阅读框（ORF），还来自当前疫苗无法捕获的刺突蛋白和核衣壳中的内部框架外 ORF。一些来自框架外 ORF 的肽在人源化小鼠模型和 COVID-19 个体中引发了 T 细胞反应，其反应超过了对经典肽的反应，包括迄今为止报道的一些最强表位。感染细胞的全蛋白质组分析表明，早期表达的病毒蛋白对 HLA-I 呈递和免疫原性的贡献更大。这些生物学见解以及框架外 ORF 表位的发现将有助于选择用于免疫监测和疫苗开发的肽。