{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T06:07:39Z","timestamp":1779170859789,"version":"3.51.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U19AI181103"],"award-info":[{"award-number":["U19AI181103"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["75N93021C00014"],"award-info":[{"award-number":["75N93021C00014"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01AI168347"],"award-info":[{"award-number":["P01AI168347"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01AI173203"],"award-info":[{"award-number":["R01AI173203"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Allergy and Infectious Diseases or the NIH"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH Public Access Policy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lung tissue-resident CD8+ T cells facilitate viral clearance and protective immunity to influenza viruses in animal models. Their role during acute human infection is not clear. Here we use bronchoalveolar lavage samples collected from human subjects naturally infected with influenza B virus to show that influenza-specific CD8+ T cells are expanded in the lower airways during acute infection and target only a few epitopes from phylogenetically conserved internal influenza virus proteins. The lower airway influenza-specific CD8+ T-cell immunodominance hierarchy is different from the hierarchy observed in matched blood samples. Transcriptional and protein-level analyses using HLA class I tetramers reveal a tissue-resident profile and less expression of cytotoxic effector molecules in lower airway influenza-specific CD8+ T cells. Collectively, our data show that high-frequency influenza-specific CD8+ T cells with a tissue-resident phenotype are found in the lower airways during viral clearance. These cells recognize a handful of conserved viral epitopes and exhibit a functional phenotype different from cells found in blood. These cells may play a role in controlling human influenza infection.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag068","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:29:05Z","timestamp":1779168545000},"source":"Crossref","is-referenced-by-count":0,"title":["Highly focused human CD8+ T-cell response in the lower airways during acute influenza infection"],"prefix":"10.1093","volume":"215","author":[{"given":"Adam","family":"Saidu","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy Chase","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]},{"name":"Center for Infectious Diseases Research, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]},{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center , Memphis, TN,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Walden","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Hua","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather M","family":"Machkovech","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, University of Wisconsin\u2013Madison , Madison, WI,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangjie","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Resha","family":"Sisti","sequence":"additional","affiliation":[{"name":"Department of Bone Marrow Transplant and Cellular Therapy, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E Kaitlynn","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Borcherding","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jackson S","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas C","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, University of Wisconsin\u2013Madison , Madison, WI,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek E","family":"Byers","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali H","family":"Ellebedy","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]},{"name":"The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]},{"name":"Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul G","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]},{"name":"Center for Infectious Diseases Research, St. Jude Children\u2019s Research Hospital , Memphis, TN,","place":["United States"]},{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center , Memphis, TN,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3860-5473","authenticated-orcid":false,"given":"Philip A","family":"Mudd","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]},{"name":"The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]},{"name":"Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine , Saint Louis, MO,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"2026051901290267600_vkag068-B1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.coviro.2020.09.006","article-title":"Anti-viral protective capacity of tissue resident memory T cells","volume":"46","author":"Paik","year":"2021","journal-title":"Curr Opin Virol"},{"key":"2026051901290267600_vkag068-B2","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1146\/annurev-immunol-042617-053214","article-title":"Tissue-resident T cells and other resident leukocytes","volume":"37","author":"Masopust","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"2026051901290267600_vkag068-B3","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.4049\/jimmunol.152.4.1653","article-title":"Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity","volume":"152","author":"Liang","year":"1994","journal-title":"J Immunol"},{"key":"2026051901290267600_vkag068-B4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1189\/jlb.0313180","article-title":"Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection","volume":"95","author":"Wu","year":"2014","journal-title":"J Leukoc Biol"},{"key":"2026051901290267600_vkag068-B5","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41586-023-06937-1","article-title":"Prevention of respiratory virus transmission by resident memory CD8+ T cells","volume":"626","author":"Uddb\u00e4ck","year":"2024","journal-title":"Nature"},{"key":"2026051901290267600_vkag068-B6","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1164\/rccm.201207-1245OC","article-title":"High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection","volume":"186","author":"Zhao","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026051901290267600_vkag068-B7","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1164\/rccm.202103-0620OC","article-title":"Innate-like gene expression of lung-resident memory CD8 + T cells during experimental human influenza: a clinical study","volume":"204","author":"Paterson","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"key":"2026051901290267600_vkag068-B8","doi-asserted-by":"crossref","first-page":"110071","DOI":"10.1016\/j.celrep.2021.110071","article-title":"Heterogeneity of human anti-viral immunity shaped by virus, tissue, age, and sex","volume":"37","author":"Poon","year":"2021","journal-title":"Cell Rep"},{"key":"2026051901290267600_vkag068-B9","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1172\/JCI96957","article-title":"Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles","volume":"128","author":"Pizzolla","year":"2018","journal-title":"J Clin Invest"},{"key":"2026051901290267600_vkag068-B10","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.4049\/jimmunol.2100294","article-title":"Comprehensive immunologic evaluation of bronchoalveolar lavage samples from human patients with moderate and severe seasonal influenza and severe COVID-19","volume":"207","author":"Reynolds","year":"2021","journal-title":"J Immunol"},{"key":"2026051901290267600_vkag068-B11","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41587-021-00989-2","article-title":"Integrating T cell receptor sequences and transcriptional profiles by clonotype neighbor graph analysis (CoNGA)","volume":"40","author":"Schattgen","year":"2022","journal-title":"Nat Biotechnol"},{"key":"2026051901290267600_vkag068-B12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"2026051901290267600_vkag068-B13","first-page":"e1012760","article-title":"scRepertoire 2: enhanced and efficient toolkit for single-cell immune profiling","volume-title":"PLoS Comput Biol","author":"Yang","year":"2025"},{"key":"2026051901290267600_vkag068-B14","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41586-020-2877-5","article-title":"Exuberant fibroblast activity compromises lung function via ADAMTS4","volume":"587","author":"Boyd","year":"2020","journal-title":"Nature"},{"key":"2026051901290267600_vkag068-B15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"2026051901290267600_vkag068-B16","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/s41467-022-28803-w","article-title":"Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data","volume":"13","author":"Ianevski","year":"2022","journal-title":"Nat Commun"},{"key":"2026051901290267600_vkag068-B17","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s42003-020-01625-6","article-title":"Mapping the immune environment in clear cell renal carcinoma by single-cell genomics","volume":"4","author":"Borcherding","year":"2021","journal-title":"Commun Biol"},{"key":"2026051901290267600_vkag068-B18","doi-asserted-by":"crossref","first-page":"4413","DOI":"10.1128\/JVI.73.5.4413-4426.1999","article-title":"Comparative analysis of evolutionary mechanisms of the hemagglutinin and three internal protein genes of influenza B virus: multiple cocirculating lineages and frequent reassortment of the NP, M, and NS genes","volume":"73","author":"Lindstrom","year":"1999","journal-title":"J Virol"},{"key":"2026051901290267600_vkag068-B19","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41590-019-0320-6","article-title":"Human CD8+ T cell cross-reactivity across influenza A, B and C viruses","volume":"20","author":"Koutsakos","year":"2019","journal-title":"Nat Immunol"},{"key":"2026051901290267600_vkag068-B20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive features define epitope-specific T cell receptor repertoires","volume":"547","author":"Dash","year":"2017","journal-title":"Nature"},{"key":"2026051901290267600_vkag068-B21","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41590-022-01395-9","article-title":"Tissue adaptation and clonal segregation of human memory T cells in barrier sites","volume":"24","author":"Poon","year":"2023","journal-title":"Nat Immunol"},{"key":"2026051901290267600_vkag068-B22","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1084\/jem.20181308","article-title":"CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways","volume":"216","author":"Wein","year":"2019","journal-title":"J Exp Med"},{"key":"2026051901290267600_vkag068-B23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.4049\/jimmunol.1402975","article-title":"Airway-resident memory CD8 T cells provide antigen-specific protection against respiratory virus challenge through rapid IFN-\u03b3 production","volume":"195","author":"McMaster","year":"2015","journal-title":"J Immunol"},{"key":"2026051901290267600_vkag068-B24","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1016\/j.immuni.2025.11.003","article-title":"Human lung CD8+ tissue-resident memory T cell\u2013derived interferon-\u03b3 orchestrates subset-specific antiviral programming in airway epithelial cells","volume":"58","author":"Mattingly","year":"2025","journal-title":"Immunity"},{"key":"2026051901290267600_vkag068-B25","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/infdis\/jiaf140","article-title":"Assessing the impact of influenza epidemics in Hong Kong","volume":"232","author":"Wong","year":"2025","journal-title":"J Infect Dis"},{"key":"2026051901290267600_vkag068-B26","doi-asserted-by":"crossref","first-page":"e580","DOI":"10.1093\/cid\/ciaf545","article-title":"Severity of clinical presentation and outcomes in hospitalized adult patients with influenza by type and subtype, United States\u20142017\u20132020","volume":"82","author":"Cleary","year":"2025","journal-title":"Clin Infect Dis"},{"key":"2026051901290267600_vkag068-B27","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1099\/vir.0.000156","article-title":"Influenza B virus\u2013specific CD8+ T-lymphocytes strongly cross-react with viruses of the opposing influenza B lineage","volume":"96","author":"van de Sandt","year":"2015","journal-title":"J Gen Virol"},{"key":"2026051901290267600_vkag068-B28","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41590-024-02072-9","article-title":"Robust mucosal SARS-CoV-2-specific T cells effectively combat COVID-19 and establish polyfunctional resident memory in patient lungs","volume":"26","author":"Zhu","year":"2025","journal-title":"Nat Immunol"},{"key":"2026051901290267600_vkag068-B29","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1128\/jvi.76.5.2567-2572.2002","article-title":"Sequence variation in a newly identified HLA-B35-restricted epitope in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes","volume":"76","author":"Boon","year":"2002","journal-title":"J Virol"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/5\/vkag068\/68332196\/vkag068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/5\/vkag068\/68332196\/vkag068.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:29:09Z","timestamp":1779168549000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/doi\/10.1093\/jimmun\/vkag068\/8687158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,14]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkag068","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,5]]},"article-number":"vkag068"}}