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

Hulin-Curtis, Sarah, Geary, James, MacLachlan, Bruce, Altmann, Danny, Baillon, Laury, Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Greenshields-Watson, Alex, Hesketh, Sophie, Humphreys, Ian ORCID: https://orcid.org/0000-0002-9512-5337, Jones, Ian, Lauder, Sarah, Mason, Georgina, Smart, Kathryn, Scourfield, Oliver, Scott, Jake, Sukhova, Ksenia, Stanton, Richard ORCID: https://orcid.org/0000-0002-6799-1182, Wall, Aaron, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Barclay, Wendy, Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 and Godkin, Andrew 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. 10.1016/j.celrep.2024.114259

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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
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	Cell Press
ISSN:	2211-1247
Funders:	Wellcome Trust
Date of First Compliant Deposit:	17 June 2024
Date of Acceptance:	7 May 2024
Last Modified:	01 Jul 2024 15:22
URI:	https://orca.cardiff.ac.uk/id/eprint/169003

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