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Peer-reviewedCC BY 4.0Scientific Reports

Prevalent α-chain–centric TCR metaclones shape specificity and focus early SARS-CoV-2 T cell responses

  • Shubham Bansal
  • Ty Bottorff
  • Peter S. Linsley
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Abstract

Chain-centric TCRs or metaclones, in which one chain pairs with diverse partners, are well documented, but their role in immunity remains unclear. Here, we characterize paired human αβ TCR datasets and show that alpha-centric TCRs are more prevalent than beta-centric TCRs across healthy and diseased individuals. Sequence modeling links alpha-centricity to shorter TRA CDR3 length, greater flexibility, and increased hydrophobicity. Alpha-centric TCRs are enriched for multi-epitope VDJdb annotation, especially for epitopes most dissimilar to each other in sequence. T cells with Spike-motif alpha-centric TCRs, including 1–2-mismatch variants, are activated in COVID-19 patients. These TCRs also share TRA junctions with CMV, EBV, and influenza-reactive TCRs, consistent with broadly cross-reactive, TRA -dominant CD4+ responses. Our findings suggest a role for TRA -dominant recognition in shaping cross-reactive CD4+ T cell immunity.

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Cite

BibTeXRIS
BibTeX
@article{bansal2026prevalent,
  title = {{Prevalent α-chain–centric TCR metaclones shape specificity and focus early SARS-CoV-2 T cell responses}},
  author = {Shubham Bansal and Ty Bottorff and Peter S. Linsley},
  journal = {Scientific Reports},
  year = {2026},
  month = oct,
  doi = {10.1038/s41598-026-73972-z},
  url = {https://www.nature.com/articles/s41598-026-73972-z},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Prevalent α-chain–centric TCR metaclones shape specificity and focus early SARS-CoV-2 T cell responses
AU  - Shubham Bansal
AU  - Ty Bottorff
AU  - Peter S. Linsley
PY  - 2026
DA  - 2026/10/01
JO  - Scientific Reports
DO  - 10.1038/s41598-026-73972-z
UR  - https://www.nature.com/articles/s41598-026-73972-z
AB  - Chain-centric TCRs or metaclones, in which one chain pairs with diverse partners, are well documented, but their role in immunity remains unclear. Here, we characterize paired human αβ TCR datasets and show that alpha-centric TCRs are more prevalent than beta-centric TCRs across healthy and diseased individuals. Sequence modeling links alpha-centricity to shorter TRA CDR3 length, greater flexibility, and increased hydrophobicity. Alpha-centric TCRs are enriched for multi-epitope VDJdb annotation, especially for epitopes most dissimilar to each other in sequence. T cells with Spike-motif alpha-centric TCRs, including 1–2-mismatch variants, are activated in COVID-19 patients. These TCRs also share TRA junctions with CMV, EBV, and influenza-reactive TCRs, consistent with broadly cross-reactive, TRA -dominant CD4+ responses. Our findings suggest a role for TRA -dominant recognition in shaping cross-reactive CD4+ T cell immunity.
SN  - 2045-2322
ER  -