Molecular basis for universal HLA-A(star)0201-restricted CD8( ) T-cell immunity against influenza viruses

Sophie A Valkenburg; Tracy M Josephs; E Bridie Clemens; Emma J Grant; Thi HO Nguyen; George C Wang; David A Price; Adrian Miller; Steven YC Tong; Paul G Thomas; Peter C Doherty; Jamie Rossjohn; Stephanie Gras; Katherine Kedzierska

Journal article

Molecular basis for universal HLA-A(star)0201-restricted CD8( ) T-cell immunity against influenza viruses

Sophie A Valkenburg, Tracy M Josephs, E Bridie Clemens, Emma J Grant, Thi HO Nguyen, George C Wang, David A Price, Adrian Miller, Steven YC Tong, Paul G Thomas, Peter C Doherty, Jamie Rossjohn, Stephanie Gras, Katherine Kedzierska

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2016

DOI: 10.1073/pnas.1603106113

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 NP41..

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University of Melbourne Researchers

Bridie Clemens Author Microbiology and Immunology

Oanh Nguyen Author Microbiology and Immunology

Jamie Rossjohn Author Microbiology and Immunology

Peter Doherty Author Microbiology and Immunology

Katherine Kedzierska Author Microbiology and Immunology

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Grants

Awarded by National Health and Medical Research Council (NHMRC)

Awarded by NHMRC

Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

Awarded by Wellcome Trust

Funding Acknowledgements

We thank Nicola Bird for technical assistance and Natalie Saunders for sorting. The C1R-B<SUP>star</SUP>3501 plasmid was provided by Dr. David Cole (Cardiff University). HLA-A2.1 transgenic HHD mice were developed and provided by Dr. Francois Lemonnier (Pasteur Institute). This work was supported by National Health and Medical Research Council (NHMRC) Project Grant 1042662 (to A.M., S.Y.C.T., and K.K.) and NHMRC Program Grant 567122 (to P.C.D. and K.K.). S.A.V. is an NHMRC Early Career Research Fellow, E.B.C. is an NHMRC Peter Doherty Fellow, D.A.P. is a Wellcome Trust Senior Investigator, S.Y.C.T. and K.K. are NHMRC Career Development Fellows, J.R. is an NHMRC Australia Fellow (AF50), and S.G. is an Australian Research Council Future Fellow (FT120100416). E.J.G. is a recipient of an NHMRC Aboriginal and Torres Strait Islander Health Research Scholarship.