CD8⁺ T-cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph

Indigenous people worldwide are at high-risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. We defined CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identified immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550-558-specific CD8+ T-cells cells being cross-reactive between IAV and IBV. Memory CD8+ T-cells towards these specificities were present in blood (CD27+CD45RA- phenotype) and tissues (CD103+CD69+ phenotype) of healthy subjects, and effector CD27-CD45RA-PD-1+CD38+CD8+ T-cells in IAV/IBV patients. Our data present the first evidence of influenza-specific CD8+ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8+ T-cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.One Sentence SummaryInfluenza-specific CD8+ T-cell specificities restricted by HLA-A*24:02.