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

Hulin-Curtis, S., Geary, J. K., MacLachlan, B. J., Altmann, D. M., Baillon, L., Cole, D. K., Greenshields-Watson, A., Hesketh, S. J., Humphreys, I. R., Jones, I. M. ORCID: https://orcid.org/0000-0002-7738-2516, Lauder, S. N., Mason, G. H., Smart, K., Scourfield, D. O., Scott, J., Sukhova, K., Stanton, R. J., Wall, A., Rizkallah, P. J., Barclay, W. S., Gallimore, A. and Godkin, A. ORCID: https://orcid.org/0000-0002-1910-7567 (2024) A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation. Cell Reports, 43 (6). 114259. ISSN 22111247 doi: 10.1016/j.celrep.2024.114259

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/116754
Identification Number/DOI	10.1016/j.celrep.2024.114259
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	Science Direct
Download/View statistics	View download statistics for this item