A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation

• Published in: Cell reports (Cambridge) Vol. 43; no. 6; p. 114259
• Main Authors: Hulin-Curtis, Sarah, Geary, James K., MacLachlan, Bruce J., Altmann, Danny M., Baillon, Laury, Cole, David K., Greenshields-Watson, Alex, Hesketh, Sophie J., Humphreys, Ian R., Jones, Ian M., Lauder, Sarah N., Mason, Georgina H., Smart, Kathryn, Scourfield, D. Oliver, Scott, Jake, Sukhova, Ksenia, Stanton, Richard J., Wall, Aaron, Rizkallah, Pierre J., Barclay, Wendy S., Gallimore, Awen, Godkin, Andrew
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-06-2024
• Subjects: Animals; CD4+ T cell; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Epitopes - immunology; Female; HLA-DR1; Humans; influenza A virus; Influenza A virus - genetics; Influenza A virus - immunology; Influenza, Human - immunology; Influenza, Human - prevention & control; Influenza, Human - virology; lung CD8+ tissue-resident memory T cell; Lymphocyte Activation - immunology; Mice; Mutation; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - virology; peptide-flanking residues; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; vaccine; lung CD8+ tissue-resident memory T cell; CP: Immunology; peptide-flanking residues; vaccine; CD4+ T cell; HLA-DR1; influenza A virus; CD4(+) T cell; lung CD8(+) tissue-resident memory T cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114259

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.
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•Modifying CD4+ T cell epitope of influenza HA transforms immunogenicity and long-term immunity•Modified HA also induces increased CD8+ T cells to influenza NP in HLA-DR1+ mice•Long-term heterosubtypic protection is mediated by antigen-specific lung CD4+ and CD8+ T cells•A single mutation of a peptide-flanking residue alters TCR-pHLA-II interface and affinity
Hulin-Curtis et al. demonstrate that a single targeted mutation in an HLA-DR1-presented epitope enhances control of primary influenza infection and long-term immunity after heterosubtypic re-challenge in HLA-DR1 mice. Enhanced protection appears to be mainly mediated by lung-derived T cells.