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

Chen, Yuan, Mason, Georgina H., Scourfield, D. Oliver, Greenshields-Watson, Alexander, Haigh, Tracey A., Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, Long, Heather M., Gallimore, Awen M. ORCID: https://orcid.org/0000-0001-6675-7004, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, MacLachlan, Bruce J. and Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567 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) , 112827. 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	2211-1247
Funders:	Wellcome Trust
Date of First Compliant Deposit:	24 July 2023
Date of Acceptance:	30 June 2023
Last Modified:	23 Sep 2023 19:56
URI:	https://orca.cardiff.ac.uk/id/eprint/161217

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