Cell Reports (Aug 2023)

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

Journal volume & issue
Vol. 42, no. 8
p. 112827

Abstract

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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.

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