{"doi":"10.1016/j.celrep.2024.114259","title":"A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation","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.","journal":"Cell Reports","year":2024,"id":446860,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1264491,"name":"James K. Geary","orcid":null,"position":1,"is_corresponding":false},{"id":1264049,"name":"Bruce J. MacLachlan","orcid":"0000-0002-2685-2733","position":2,"is_corresponding":false},{"id":1264492,"name":"Danny M. Altmann","orcid":null,"position":3,"is_corresponding":false},{"id":1264050,"name":"Laury Baillon","orcid":"0000-0001-6961-4519","position":4,"is_corresponding":false},{"id":1042535,"name":"David K. Cole","orcid":"0000-0003-0028-9396","position":5,"is_corresponding":false},{"id":1264493,"name":"Alex Greenshields-Watson","orcid":null,"position":6,"is_corresponding":false},{"id":1264051,"name":"Sophie J. Hesketh","orcid":"0000-0002-3107-8842","position":7,"is_corresponding":false},{"id":555702,"name":"Ian R. Humphreys","orcid":"0000-0002-9512-5337","position":8,"is_corresponding":false},{"id":605599,"name":"Ian M. Jones","orcid":"0000-0002-7738-2516","position":9,"is_corresponding":false},{"id":1264052,"name":"Sarah N. Lauder","orcid":"0000-0003-2561-6277","position":10,"is_corresponding":false},{"id":1264053,"name":"Georgina H. Mason","orcid":"0000-0002-7844-7190","position":11,"is_corresponding":false},{"id":1264054,"name":"Kathryn Smart","orcid":"0000-0002-5445-007X","position":12,"is_corresponding":false},{"id":1264494,"name":"D. Oliver Scourfield","orcid":null,"position":13,"is_corresponding":false},{"id":1000413,"name":"Jake Scott","orcid":"0000-0003-4210-509X","position":14,"is_corresponding":false},{"id":1198898,"name":"Ksenia Sukhova","orcid":"0000-0003-3678-5631","position":15,"is_corresponding":false},{"id":472910,"name":"Richard J. Stanton","orcid":"0000-0002-6799-1182","position":16,"is_corresponding":false},{"id":1264495,"name":"Aaron Wall","orcid":null,"position":17,"is_corresponding":false},{"id":1264496,"name":"Pierre J. Rizkallah","orcid":null,"position":18,"is_corresponding":false},{"id":84268,"name":"William Barclay","orcid":"0000-0002-3948-0895","position":19,"is_corresponding":false},{"id":1264055,"name":"Awen Gallimore","orcid":"0000-0001-6675-7004","position":20,"is_corresponding":false},{"id":1264056,"name":"Andrew Godkin","orcid":"0000-0002-1910-7567","position":21,"is_corresponding":false},{"id":1264048,"name":"Sarah L. Hulin-Curtis","orcid":"0000-0003-0889-964X","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T02:01:54.980444Z","pmid":"38819988","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}