Distinct CD8⁺ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2⁺ Patients

Although emerging data have revealed the critical role of memory CD8⁺ T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8⁺ T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8⁺ T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8⁺ T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8⁺ T-cell types including cytotoxic KLRB1 ⁺ CD8αα cells with innate-like T-cell signatures, IFNG ^hi ID3 ^hi memory cells and IL7R ⁺ proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activated FASL ^hi T-cell subsets and early-terminated or dysfunctional IL4R ⁺ GATA3 ⁺ stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8⁺ T-cell profiles may dictate COVID-19 severity.