Unveiling structural determinants of peptide recognition by public and private SARS-CoV-2-specific T-cell receptors.
11 affiliations
- 1Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- 2Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- 3MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
- 4Institute for Advanced Study in Physics, Zhejiang University, Hangzhou, Zhejiang, China.
- 5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- 6Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
- 7Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
- 8MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. [email protected].
- 9Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
- 10Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
- 11Diamond Light Source, Harwell Science and Innovation Campus, Didcot, UK. [email protected].
Abstract
Public T cell receptors (TCRs) recurrently emerge across individuals in response to common pathogens, yet the structural and biophysical basis distinguishing public from private clonotypes remains incompletely defined. Here, we combine epitope mapping, single-cell TCR sequencing, and single-particle cryo-electron microscopy to dissect CD8⁺ T cell responses to the immunodominant SARS-CoV-2 ORF3a₍₂₀₇₋₂₁₅₎ epitope presented by HLA-A*01:01. Among responding clonotypes, we identify a public TCR (TCRpub), shared across donors, and a private TCR (TCRpriv) that uses nearly identical β chains but distinct α chains. Despite comparable micromolar affinities and functional avidities, cryo-EM structures at ~3 Å resolution reveal that the two receptors engage the peptide-MHC complex through distinct CDR-loop configurations and contact footprints. TCRpub establishes contacts with the peptide and the MHC α2-helix primarily through the CDR2β and CDR3β loops, whereas TCRpriv distributes contacts across both MHC α-helices and engages the peptide via multiple CDR loops. In agreement with these observations, alanine-scanning mutagenesis reveals that TCRpub shows greater sensitivity to peptide substitutions, consistent with its peptide-focused binding mode. These findings demonstrate how alternative α-chain pairing reconfigures the antigen-binding interface within a shared β-chain.
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BibTeX
@article{akıl2026unveiling,
title = {{Unveiling structural determinants of peptide recognition by public and private SARS-CoV-2-specific T-cell receptors.}},
author = {Caner Akıl and Yanchun Peng and Julia McCarthy and Yanan Zhu and Nathan Hardenbrook and Yunkai Yang and Danning Dong and Elie Antoun and Xuan Yao and Guihai Liu and Ji-Li Chen and Esra Balıkçı and Raul Cioaca and Alexander J Mentzer and Julian C Knight and Ricardo A Fernandes and Tao Dong and Peijun Zhang},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77827-z},
url = {https://europepmc.org/article/MED/42907447},
note = {CC BY},
}
RIS
TY - JOUR
TI - Unveiling structural determinants of peptide recognition by public and private SARS-CoV-2-specific T-cell receptors.
AU - Caner Akıl
AU - Yanchun Peng
AU - Julia McCarthy
AU - Yanan Zhu
AU - Nathan Hardenbrook
AU - Yunkai Yang
AU - Danning Dong
AU - Elie Antoun
AU - Xuan Yao
AU - Guihai Liu
AU - Ji-Li Chen
AU - Esra Balıkçı
AU - Raul Cioaca
AU - Alexander J Mentzer
AU - Julian C Knight
AU - Ricardo A Fernandes
AU - Tao Dong
AU - Peijun Zhang
PY - 2026
DA - 2026/09/22
JO - Nature communications
DO - 10.1038/s41467-026-77827-z
UR - https://europepmc.org/article/MED/42907447
AB - Public T cell receptors (TCRs) recurrently emerge across individuals in response to common pathogens, yet the structural and biophysical basis distinguishing public from private clonotypes remains incompletely defined. Here, we combine epitope mapping, single-cell TCR sequencing, and single-particle cryo-electron microscopy to dissect CD8⁺ T cell responses to the immunodominant SARS-CoV-2 ORF3a₍₂₀₇₋₂₁₅₎ epitope presented by HLA-A*01:01. Among responding clonotypes, we identify a public TCR (TCRpub), shared across donors, and a private TCR (TCRpriv) that uses nearly identical β chains but distinct α chains. Despite comparable micromolar affinities and functional avidities, cryo-EM structures at ~3 Å resolution reveal that the two receptors engage the peptide-MHC complex through distinct CDR-loop configurations and contact footprints. TCRpub establishes contacts with the peptide and the MHC α2-helix primarily through the CDR2β and CDR3β loops, whereas TCRpriv distributes contacts across both MHC α-helices and engages the peptide via multiple CDR loops. In agreement with these observations, alanine-scanning mutagenesis reveals that TCRpub shows greater sensitivity to peptide substitutions, consistent with its peptide-focused binding mode. These findings demonstrate how alternative α-chain pairing reconfigures the antigen-binding interface within a shared β-chain.
SN - 2041-1723
ER -