Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

Yuan Chen; Georgina Mason; D Oliver Scourfield; Alexander Greenshields-Watson; Tracey Haigh; Andrew Sewell; Heather Long; Awen Gallimore; Pierre Rizkallah; Bruce MacLachlan; Andrew Godkin

doi:10.1016/j.celrep.2023.112827

Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4⁺ T cell immunity

Yuan Chen, Georgina Mason, D Oliver Scourfield, Alexander Greenshields-Watson, Tracey Haigh, Andrew Sewell, Heather Long, Awen Gallimore, Pierre Rizkallah, Bruce MacLachlan^*, Andrew Godkin

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	112827
Number of pages	22
Journal	Cell Reports
Volume	42
Issue number	8
Early online date	19 Jul 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.112827
Publication status	Published - 29 Aug 2023

Bibliographical note

Acknowledgments:
This work was funded by a Sêr Cymru–Tackling COVID-19 Award from the Welsh Government/Llywodraeth Cymru to B.J.M. and A.G. The authors would like to thank the blood donors for their contribution to this work. The authors would like to thank Diamond Light Source for beamtime (proposals mx20147, mx29502, and mx29990) and the staff of beamlines i04 and i04-1 for assistance with data collection. B.J.M. is a recipient of a Health and Care Research Wales–Health Research Fellowship (HF-21-1886). A.G. and A.M.G. are supported by a Wellcome Trust Collaborative Award in Science (209213/Z/17/Z). H.M.L. was supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by NIHR/MRC MR/V028448/1.

Keywords

T cells
CD4+ T cells
SARS-CoV-2
coronavirus
COVID-19
HLA class II
antigen presentation
immune escape
immune memory
crystallography

Access to Document

10.1016/j.celrep.2023.112827Licence: Creative Commons: Attribution (CC BY)

ChenY2023Structural Final published version, 5.16 MBLicence: Creative Commons: Attribution (CC BY)

A UK underpinning platform to study immunology and immunopathology of COVID-19:The UK Coronavirus Immunology Consortium
Duggal, N., Zuo, J., Moss, P., Long, H., Lord, J., Taylor, G. & Wraith, D.
Medical Research Council
20/08/20 → 31/10/22
Project: Research Councils

Cite this

Chen, Y., Mason, G., Scourfield, D. O., Greenshields-Watson, A., Haigh, T., Sewell, A., Long, H., Gallimore, A., Rizkallah, P., MacLachlan, B., & Godkin, A. (2023). Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4⁺ T cell immunity. Cell Reports, 42(8), Article 112827. https://doi.org/10.1016/j.celrep.2023.112827

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abstract = "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.",

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AU - Gallimore, Awen

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N1 - Acknowledgments: This work was funded by a Sêr Cymru–Tackling COVID-19 Award from the Welsh Government/Llywodraeth Cymru to B.J.M. and A.G. The authors would like to thank the blood donors for their contribution to this work. The authors would like to thank Diamond Light Source for beamtime (proposals mx20147, mx29502, and mx29990) and the staff of beamlines i04 and i04-1 for assistance with data collection. B.J.M. is a recipient of a Health and Care Research Wales–Health Research Fellowship (HF-21-1886). A.G. and A.M.G. are supported by a Wellcome Trust Collaborative Award in Science (209213/Z/17/Z). H.M.L. was supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by NIHR/MRC MR/V028448/1.

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N2 - 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.

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