Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2

SARS-CoV-2-specific CD8⁺ T cells are scarce but detectable in unexposed healthy donors (UHDs). It remains unclear whether pre-existing human coronavirus (HCoV)-specific CD8⁺ T cells are converted to functionally competent T cells cross-reactive to SARS-CoV-2. Here, we identified the HLA-A24-high binding, immunodominant epitopes in SARS-CoV-2 spike region that can be recognized by seasonal coronavirus-specific CD8⁺ T cells from HLA-A24⁺ UHDs. Cross-reactive CD8⁺ T cells were clearly reduced in patients with hematological malignancy, who are usually immunosuppressed, compared to those in UHDs. Furthermore, we showed that CD8⁺ T cells in response to a selected dominant epitope display multifunctionality and cross-functionality across HCoVs in HLA-A24⁺ donors. Cross-reactivity of T-cell receptors isolated from them exhibited selective diversity at the single-cell level. Taken together, when stimulated well by immunodominant epitopes, selective pre-existing CD8⁺ T cells with high functional avidity may be cross-reactive against SARS-CoV-2.