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

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. [Display omitted] •The RNA-dependent RNA-polymerase is highly conserved among human coronaviruses•CD8+ T cells from unexposed donors recognize SARS-CoV-2 polymerase epitopes•TCR engineered T cells kill target cell lines that express the polymerase•Polymerase-reactive TCRs cross-react with seasonal coronaviruses Nesterenko et al. identify T cell responses with potential to confer long-term immunity against SARS-CoV-2. The machinery responsible for replicating the viral genome is highly conserved and, as shown by Nesterenko et al., can be effectively targeted by CD8+ T cells.