Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians.
Indigenous populations, including Indigenous Australians, are highly susceptible to severe influenza disease and the underlying mechanisms are unknown. We studied immune and genetic factors that could predicate severe influenza disease in Indigenous Australians enrolled in the LIFT study: looking into influenza T-cell immunity. To examine CD8(+) T-cell immunity, we characterised human leukocyte antigen (HLA) profiles. HLA typing confirmed previous studies showing predominant usage of HLA-A*02:01, 11:01, 24:02, 34:01 and HLA-B*13:01, 15:21, 40:01/02, 56:01/02 in Indigenous Australians. We identified two new HLA alleles (HLA-A*02:new and HLA-B*56:new). Modelling suggests that variations within HLA-A*02:new (but not HLA-B56:new) could affect peptide binding. There is a relative lack of known influenza epitopes for the majority of these HLAs, with the exception of a universal HLA-A*02:01-M158 epitope and proposed epitopes presented by HLA-A*11:01/HLA-A*24:02. To dissect universal CD8(+) T-cell responses, we analysed the magnitude, function and T-cell receptor (TCR) clonality of HLA-A*02:01-M158(+)CD8(+) T cells. We found comparable IFN-γ, TNF and CD107a and TCRαβ characteristics in Indigenous and non-Indigenous Australians, suggesting that the ~15% of Indigenous people that express HLA-A*02:01 have universal influenza-specific CD8(+) T-cell immunity. Furthermore, the frequency of an influenza host risk factor, IFITM3-C/C, was comparable between Indigenous Australians and Europeans, suggesting that expression of this allele does not explain increased disease severity at a population level. Our study indicates a need to identify novel influenza-specific CD8(+) T-cell epitopes restricted by HLA-A and HLA-B alleles prevalent in Indigenous populations for the rational design of universal T-cell vaccines.
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
E Bridie
EB
Clemens
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Emma J
EJ
Grant
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Zhongfang
Z
Wang
Infection and Immunity Program, Biomedicine Discovery Institute and The Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
Stephanie
S
Gras
Menzies School of Health Research, Darwin, Northern Territory, Australia.
Peta
P
Tipping
Infection and Immunity Program, Biomedicine Discovery Institute and The Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.|Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Jamie
J
Rossjohn
Indigenous Research Network, Griffith University, Brisbane, Queensland, Australia.
Adrian
A
Miller
Menzies School of Health Research, Darwin, Northern Territory, Australia.
Steven Y C
SY
Tong
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Katherine
K
Kedzierska
D000328:Adult; D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D006650:Histocompatibility Testing; D006801:Humans; D007252:Influenza Vaccines; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D016601:RNA-Binding Proteins / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; C080082:IFITM3 protein, human; D007252:Influenza Vaccines; D052118:Lysosomal-Associated Membrane Protein 1; C488936:M1 protein, Influenza A virus; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; D007371:Interferon-gamma