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. 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. Cheng, Michael 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 and Katherine Kedzierska ()
Additional contact information
Luca Hensen: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Patricia T. Illing: Biomedicine Discovery Institute, Monash University
E. Bridie Clemens: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Thi H. O. Nguyen: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Marios Koutsakos: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Carolien E. Sandt: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Nicole A. Mifsud: Biomedicine Discovery Institute, Monash University
Andrea T. Nguyen: Biomedicine Discovery Institute, Monash University
Christopher Szeto: Biomedicine Discovery Institute, Monash University
Brendon Y. Chua: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Hanim Halim: Biomedicine Discovery Institute, Monash University
Simone Rizzetto: UNSW Sydney
Fabio Luciani: UNSW Sydney
Liyen Loh: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Emma J. Grant: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Phillipa M. Saunders: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Andrew G. Brooks: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Steve Rockman: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Tom C. Kotsimbos: Immunology and Respiratory Medicine, The Alfred Hospital
Allen C. Cheng: Monash University
Michael Richards: Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Glen P. Westall: Lung Transplant Unit, Alfred Hospital
Linda M. Wakim: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Thomas Loudovaris: Immunology and Diabetes Unit, St Vincent’s Institute of Medical Research
Stuart I. Mannering: Immunology and Diabetes Unit, St Vincent’s Institute of Medical Research
Michael Elliott: University of Sydney
Stuart G. Tangye: Garvan Institute of Medical Research
David C. Jackson: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Katie L. Flanagan: Launceston General Hospital
Jamie Rossjohn: Biomedicine Discovery Institute, Monash University
Stephanie Gras: Biomedicine Discovery Institute, Monash University
Jane Davies: Menzies School of Health Research
Adrian Miller: CQUniversity
Steven Y. C. Tong: Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Anthony W. Purcell: Biomedicine Discovery Institute, Monash University
Katherine Kedzierska: University of Melbourne, at the Peter Doherty Institute for Infection and Immunity

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-23212-x

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