CD8+ T-cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph
Author:
Hensen Luca, Illing Patricia T., Clemens E. Bridie, Nguyen Thi H.O., Koutsakos Marios, van de Sandt Carolien E., Mifsud Nicole A., Nguyen Andrea, Szeto Christopher, Chua Brendon Y., Halim Hanim, Rizzetto Simone, Luciani Fabio, Loh Liyen, Grant Emma J., Saunders Phillipa M., Brooks Andrew G, Rockman Steve, Kotsimbos Tom C., Cheng Allen C., Richards Michael, Westall Glen P., Wakim Linda M., Loudovaris Thomas, Mannering Stuart I., Elliott Michael, Tangye Stuart G., Jackson David C, Flanagan Katie L, Rossjohn Jamie, Gras Stephanie, Davies Jane, Miller Adrian, Tong Steven Y.C.ORCID, Purcell Anthony W., Kedzierska Katherine
Abstract
ABSTRACTIndigenous 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.
Publisher
Cold Spring Harbor Laboratory
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