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. Abstract Figure Graphical abstract. SARS-CoV-2 epitope-specific CD8 + T-cell subtypes associated with mild or severe COVID-19 patients. Potent memory CD8 + T-cell subtypes with gene signature in mild COVID-19 patients (upper) and dysfunctional CD8 + T-cell subtypes with gene signature in severe COVID-19 patients (lower).