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

Hulin-Curtis, Sarah L ORCID: 0000-0003-0889-964X, 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 and Godkin, Andrew (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). p. 114259. doi:10.1016/j.celrep.2024.114259

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Text 14141 Hulin-Curtis, Geary, MacLachlan et al. (2024) A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (5MB) | Preview

Abstract

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
Article Type:	Article
Uncontrolled Keywords:	CD4+ T cell; Influenza A virus; HLA-DR1; Peptide-flanking residues; Lung CD8+ tissue-resident memory T cell; Vaccine
Subjects:	Q Science > QR Microbiology > QR180 Immunology Q Science > QR Microbiology > QR355 Virology R Medicine > R Medicine (General)
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Health, Life Sciences, Sport and Wellbeing
Depositing User:	Sarah Curtis
Date Deposited:	18 Jun 2024 08:45
Last Modified:	18 Jun 2024 08:45
URI:	https://eprints.glos.ac.uk/id/eprint/14141

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