CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Center for Virology, Medical University of Vienna, Vienna, Austria.
Sci Immunol. 2021 Mar 4;6(57). doi: 10.1126/sciimmunol.abg6461.
CD8 T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8 T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8 T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8 T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8 T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
CD8 T 细胞对 SARS-CoV-2 的免疫反应与 COVID-19 的严重程度和病毒控制有关。在这里，我们通过对 747 株 SARS-CoV-2 病毒分离株进行深度测序，鉴定了 MHC-I 限制的 CD8 T 细胞表位中的非同义突变。在无细胞体外测定中，突变肽表现出 MHC-I 结合能力降低或丧失。突变肽的 MHC-I 结合减少与从 HLA 匹配的 COVID-19 患者中分离的 CD8 T 细胞增殖、IFN-γ 产生和细胞毒性活性降低有关。从 COVID-19 患者中分离的体外扩增、四聚体分选的 CD8 T 细胞的单细胞 RNA 测序进一步揭示了对突变肽的转录反应的定性差异。我们的研究结果强调了 SARS-CoV-2 通过 MHC-I 限制的病毒表位中的点突变来规避 CD8 T 细胞监测的能力。
