HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses

• DOI: 10.1016/j.celrep.2021.110167
• Publication Date: 2021-12-10T02:48:12Z
• Authors: Pavlo A. Nesterenko; Jami McLaughlin; Brandon L. Tsai; Giselle Burton Sojo; Donghui Cheng; Daniel Zhao; Zhiyuan Mao; Nathanael J. Bang...; Matthew B. Obusan; Yapeng Su; Rachel H. Ng; William Chour; Jingyi Xie; Yan-Ruide Li; Derek Lee; Miyako Noguchi; Camille Carmona; John W. Phillips; Jocelyn T. Kim; Lili Yang; James R. Heath; Paul C. Boutros; Owen N. Witte
• Keywords: Coronavirus

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.