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 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
Affiliations
Yuan Chen
Division 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
Georgina H. Mason
Division 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
D. Oliver Scourfield
Division 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
Alexander Greenshields-Watson
Division 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
Tracey A. Haigh
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Andrew K. Sewell
Division 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
Heather M. Long
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Awen M. Gallimore
Division 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
Pierre Rizkallah
Division 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
Bruce J. MacLachlan
Division 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 author
Andrew Godkin
Division 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 author
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.
