Human Leukocyte Antigen E (HLA-E) restricted T-cells could contribute to the control of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection alongside classical T cells. According to this study, ISARIC4C described five peptides from SARS-CoV-2 that elicited HLA-E-restricted CD8+ T cell responses in convalescent patients with coronavirus disease 2019. HLA-E peptide-specific CD8+ T cell clones, which expressed diverse T cell receptors, suppressed SARS-CoV-2 replication in Calu-3 human lung epithelial cells. Pathogen-specific CD8+ T cell responses restricted by the non-polymorphic non-classical class Ib molecule HLA-E are rarely reported in viral infections.