Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity
Summary: 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008380 |
| _version_ | 1827855639454416896 |
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| author | Yuan Chen Georgina H. Mason D. Oliver Scourfield Alexander Greenshields-Watson Tracey A. Haigh Andrew K. Sewell Heather M. Long Awen M. Gallimore Pierre Rizkallah Bruce J. MacLachlan Andrew Godkin |
| author_facet | Yuan Chen Georgina H. Mason D. Oliver Scourfield Alexander Greenshields-Watson Tracey A. Haigh Andrew K. Sewell Heather M. Long Awen M. Gallimore Pierre Rizkallah Bruce J. MacLachlan Andrew Godkin |
| author_sort | Yuan Chen |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T11:53:50Z |
| format | Article |
| id | doaj.art-89d593fdc3ac46c694db2226da7cae58 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:50Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-89d593fdc3ac46c694db2226da7cae582023-08-31T05:01:45ZengElsevierCell Reports2211-12472023-08-01428112827Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunityYuan Chen0Georgina H. Mason1D. Oliver Scourfield2Alexander Greenshields-Watson3Tracey A. Haigh4Andrew K. Sewell5Heather M. Long6Awen M. Gallimore7Pierre Rizkallah8Bruce J. MacLachlan9Andrew Godkin10Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKInstitute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKInstitute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UKDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Corresponding authorDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Department of Gastroenterology & Hepatology, University Hospital of Wales, Cardiff CF14 4XW, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723008380CP: Immunology |
| spellingShingle | Yuan Chen Georgina H. Mason D. Oliver Scourfield Alexander Greenshields-Watson Tracey A. Haigh Andrew K. Sewell Heather M. Long Awen M. Gallimore Pierre Rizkallah Bruce J. MacLachlan Andrew Godkin Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity Cell Reports CP: Immunology |
| title | Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity |
| title_full | Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity |
| title_fullStr | Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity |
| title_full_unstemmed | Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity |
| title_short | Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity |
| title_sort | structural definition of hla class ii presented sars cov 2 epitopes reveals a mechanism to escape pre existing cd4 t cell immunity |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008380 |
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