Distinct CD8⁺ T cell types associated with COVID-19 severity in unvaccinated HLA-A2⁺ patients

Despite emerging studies about coronavirus disease 2019 (COVID-19)-associated adaptive immune responses, CD8⁺ T cell immunity in the context of HLA restriction, particularly in unvaccinated patients, remains largely uncharacterized. Here, we show that in HLA-A2-positive patients with COVID-19, cell-mediated immune responses are crucial in determining disease severity, irrespective of humoral immune responses. We observe robust cell-mediated immune responses against our selected, highly conserved 9-mer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epitopes in mild patients but poor responsiveness in severe patients. Single-cell analyses of HLA-A2-restricted CD8⁺ T cells against those epitopes reveal distinct cellular profiles between mild and severe COVID-19. In mild COVID-19, effector KLRB1 ⁺ innate-like cells, IFNG ^hi ID3 ^hi memory cells, and IL7R ⁺ proliferative stem cell-like memory cells are preferentially detected. By contrast, severe cases are featured by dysfunctional T cell types, particularly early terminated and terminally differentiated subtypes. Thus, our findings suggest that contrasting HLA-A2-restricted SARS-CoV-2 epitope-specific CD8⁺ T cell profiles reflect the magnitude of cellular immune responses, potentially affecting disease severity.