title: Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses.
abstract: Memory CD8(+)T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158and the hypervariable HLA-B*3501-NP418antigens. The TCRαβs for HLA-B*3501-NP418 (+)CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19(+)TCRαβ was selected in HLA-A*0201(+)donors responding to M158 This public TCR cross-recognized naturally occurring M158variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19(+)TCR specificity for the WT and mutant M158peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201(+)individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158 Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Valkenburg
authors.affiliation: Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Josephs
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: E Bridie
authors.initials: EB
authors.lastname: Clemens
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Grant
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Thi H O
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: George C
authors.initials: GC
authors.lastname: Wang
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Indigenous Research Network, Griffith University, Brisbane, QLD 4111 Australia;
authors.forename: Adrian
authors.initials: A
authors.lastname: Miller
authors.affiliation: Menzies School of Health Research, Darwin, NT 0810, Australia;
authors.forename: Steven Y C
authors.initials: SY
authors.lastname: Tong
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105; pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.affiliation: Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Infection and Immunity Program, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au stephanie.gras@monash.edu kkedz@unimelb.edu.au.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004285:Dogs; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory / Q000235:genetics; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: D000956:Antigens, Viral; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins
keywords: T-cell receptor; human CD8+ T cells; influenza infection