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

Luca Hensen, Patricia T. Illing, E. Bridie Clemens, Thi H.O. Nguyen, Marios Koutsakos, Carolien E. van de Sandt, Nicole A. Mifsud, Andrea T. Nguyen, Christopher Szeto, Brendon Y. Chua, Hanim Halim, Simone Rizzetto, Fabio Luciani, Liyen Loh, Emma J. Grant, Phillipa M. Saunders, Andrew G. Brooks, Steve Rockman, Tom C. Kotsimbos, Allen C. ChengMichael Richards, Glen P. Westall, Linda M. Wakim, Thomas Loudovaris, Stuart I. Mannering, Michael Elliott, Stuart G. Tangye, David C. Jackson, Katie L. Flanagan, Jamie Rossjohn, Stephanie Gras, Jane Davies, Adrian Miller, Steven Y.C. Tong, Anthony W. Purcell, Katherine Kedzierska

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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+ 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 CD27CD45RAPD-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.

Original languageEnglish
Article number2931
Number of pages20
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 18 May 2021

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