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 -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.
HHD-A24 transgenic HHD mice were developed by Dr. Francois Lemonnier (Pasteur Institute, Paris, France). We thank the Monash Macromolecular Crystallization Facility staff and the staff at the Australian synchrotron for technical assistance. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. The Australian National Health and Medical Research Council (NHMRC) Program Grant (#1071916) to K.K., NHMRC Project Grant (#1122524) to K.K., S.T., A.M., S.G., and A.W.P., and NHMRC Investigator Grant (#1173871) to K.K. supported this work. This work was also supported by NIAID UO1 grant 1U01AI144616-01; Dissection of Influenza Vaccination and Infection for Childhood Immunity (DIVINCI) to K.K. and by the ARC grant # DP190103282 to K.K., A.G.B., and L.L. L.H. was a recipient of Melbourne International Research Scholarship and Melbourne International Fee Remission Scholarship. C.E.S. had received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skodowska-Curie grant agreement (#792532). J.R. is supported by an ARC Laureate fellowship. S.G. is an NHMRC SRF-A Fellow (#1159272). E.B.C. is NHMRC Peter Doherty Fellow. A.W.P. is supported by an NHMRC Principal Research Fellowship (#1137739) and NHMRC Project grant (#1085018) to A.W.P., N.A.M., and T.C.K. S.T. is an NHMRC Career Development Fellow (#1145033). E.J.G. is an NHMRC CJ Martin Fellow. P.T.I. was supported by an NHMRC Early Career Fellowship (#1072159) and Monash University Faculty of Medicine, Nursing and Health Sciences Senior Postdoctoral Fellowship (2020).
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