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

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.