Nat.Commun. Challenging immunodominance of influenza-specific CD8+ T cell responses restricted by the risk-associated HLA-A*68:01 allomorph

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Nat Commun. 2019 Dec 6;10(1):5579. doi: 10.1038/s41467-019-13346-4. Challenging immunodominance of influenza-specific CD8⁺ T cell responses restricted by the risk-associated HLA-A*68:01 allomorph.

van de Sandt CE^1,2, Clemens EB¹, Grant EJ^1,3, Rowntree LC¹, Sant S¹, Halim H⁴, Crowe J⁵, Cheng AC^6,7, Kotsimbos TC^8,9, Richards M¹⁰, Miller A^11,12, Tong SYC^10,13, Rossjohn J^4,14,15, Nguyen THO¹, Gras S^4,14, Chen W¹⁶, Kedzierska K¹⁷.
Author information

1 Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute, Melbourne, VIC, 3000, Australia. 2 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066CX, Amsterdam, Netherlands. 3 Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Infection and Immunity Program, Monash University, Clayton, VIC, 3800, Australia. 4 Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. 5 Deepdene Surgery, Deepdene, VIC, 3103, Australia. 6 School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. 7 Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC, 3004, Australia. 8 Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, VIC, 3004, Australia. 9 Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, VIC, 3004, Australia. 10 Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, 3050, Australia. 11 Indigenous Research Network, Griffith University, Brisbane, QLD, 4222, Australia. 12 Office of Indigenous Engagement, CQUniversity, Townsvillle, QLD, Australia. 13 Menzies School of Health Research, Charles Darwin University, Darwin, NT, 0811, Australia. 14 Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia. 15 Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom. 16 Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia. 17 Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute, Melbourne, VIC, 3000, Australia. kkedz@unimelb.edu.au.

Abstract

Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8⁺ T cells to mount robust responses. We elucidate the HLA-A*68:01⁺CD8⁺ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP₁₄₅⁺CD8⁺ T cell responses. Dissecting A68/NP₁₄₅⁺CD8⁺ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP₁₄₅⁺CD8⁺ memory T cells with clonally expanded TCRαβs, while low-responders display A68/NP₁₄₅⁺CD8⁺ T cells with predominantly na?ve phenotypes and non-expanded TCRαβs. Single-cell index sorting and TCRαβ analyses link expansion of A68/NP₁₄₅⁺CD8⁺ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8⁺ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8⁺ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.


PMID: 31811120 DOI: 10.1038/s41467-019-13346-4
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