| Affiliations | Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia; Department of Biochemistry and Molecular Biology & Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; School of Medical Sciences and The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Seqirus, Parkville, VIC, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, VIC, Australia; Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, VIC, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Austral... | |
| Abstract | 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<sup>+</sup> 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<sup>+</sup> T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2<sub>550-558</sub>-specific CD8<sup>+</sup> T cells being cross-reactive between IAV and IBV. Memory CD8<sup>+</sup> T cells towards these specificities are present in blood (CD27<sup>+</sup>CD45RA<sup>-</sup> phenotype) and tissues (CD103<sup>+</sup>CD69<sup>+</sup> phenotype) of healthy individuals, and effector CD27<sup>-</sup>CD45RA<sup>-</sup>PD-1<sup>+</sup>CD38<sup>+</sup>CD8<sup>+</sup> T cells in IAV/IBV patients. Our data show influenza-specific CD8<sup>+</sup> T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8<sup>+</sup> T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease. | |