- Nesterenko, Pavlo A;
- McLaughlin, Jami;
- Tsai, Brandon L;
- Burton Sojo, Giselle;
- Cheng, Donghui;
- Zhao, Daniel;
- Mao, Zhiyuan;
- Bangayan, Nathanael J;
- Obusan, Matthew B;
- Su, Yapeng;
- Ng, Rachel H;
- Chour, William;
- Xie, Jingyi;
- Li, Yan-Ruide;
- Lee, Derek;
- Noguchi, Miyako;
- Carmona, Camille;
- Phillips, John W;
- Kim, Jocelyn T;
- Yang, Lili;
- Heath, James R;
- Boutros, Paul C;
- Witte, Owen N
Cross-reactivity and direct killing of target cells remain underexplored for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA polymerase (RdRp/NSP12) as highly conserved, likely due to its critical role in the virus life cycle. We perform single-cell TCRαβ sequencing in human leukocyte antigen (HLA)-A∗02:01-restricted, RdRp-specific T cells from SARS-CoV-2-unexposed individuals. Human T cells expressing these TCRαβ constructs kill target cell lines engineered to express full-length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses. Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses.