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CD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph

Hensen, Luca, Illing, Patricia T., Bridie Clemens, E., Nguyen, Thi H. O., Koutsakos, Marios, van de Sandt, Carolien E., Mifsud, Nicole A., Nguyen, Andrea T., 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., Purcell, Anthony W. and Kedzierska, Katherine 2021. CD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph. Nature Communications 12 (1) , 2931. 10.1038/s41467-021-23212-x

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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/PB2550–558-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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 17 June 2021
Date of Acceptance: 19 April 2021
Last Modified: 18 Jun 2021 14:15

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