A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4 T cell activation.
Sarah Hulin-Curtis, James K Geary, Bruce J MacLachlan, Danny M Altmann, Laury Baillon, David K Cole, Alex Greenshields-Watson, Sophie J Hesketh, Ian R Humphreys, Ian M Jones, Sarah N Lauder, Georgina H Mason, Kathryn Smart, D Oliver Scourfield, Jake Scott, Ksenia Sukhova, Richard J Stanton, Aaron Wall, Pierre J Rizkallah, Wendy S Barclay, Awen Gallimore, Andrew Godkin
Author Information
Sarah Hulin-Curtis: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
James K Geary: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: gearyj2@cardiff.ac.uk.
Bruce J MacLachlan: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Danny M Altmann: Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
Laury Baillon: Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
David K Cole: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Alex Greenshields-Watson: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Department of Statistics, University of Oxford, Oxford OX1 3LB, UK.
Sophie J Hesketh: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Ian R Humphreys: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Ian M Jones: School of Biological Sciences, University of Reading, Reading RG6 6AH, UK.
Sarah N Lauder: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Georgina H Mason: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Kathryn Smart: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
D Oliver Scourfield: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Jake Scott: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Ksenia Sukhova: Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
Richard J Stanton: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Aaron Wall: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Pierre J Rizkallah: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Wendy S Barclay: Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
Awen Gallimore: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Andrew Godkin: Division of Infection and Immunity/Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: godkinaj@cardiff.ac.uk.
CD4 T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to "tune" CD4 T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4 and CD8 T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4 T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.
