CD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A24:02 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. The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8 + T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.