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. Here, we define 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 identify immunodominant protective CD8⁺ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2_550–558-specific CD8⁺ T cells being cross-reactive between IAV and IBV. Memory CD8⁺ T cells towards these specificities are present in blood (CD27⁺CD45RA⁻ phenotype) and tissues (CD103⁺CD69⁺ phenotype) of healthy individuals, and effector CD27⁻CD45RA⁻PD-1⁺CD38⁺CD8⁺ T cells in IAV/IBV patients. Our data show 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.