Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology

Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology Paul Thomas, Robert Mettelman, Aisha Souquette, Lee-Ann Van De Velde, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2371124/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Aug, 2023 Read the published version in Nature Immunology → Version 1 posted You are reading this latest preprint version Abstract Influenza viruses remain a leading cause of global respiratory illness in humans. The suboptimal effectiveness of seasonal influenza vaccination underscores the need for a more comprehensive understanding of immune mediators of protection, especially in populations with diverse baseline immune profiles and exposure histories. While anti-influenza antibody titers are typically used to define correlates of protection, mounting evidence suggests a substantive role for innate and cellular immunity in determining tolerance and resistance during influenza virus infection. However, distinct cell subsets that correlate with protection against symptomatic influenza remain to be identified in humans. Here, we measured baseline cellular and serologic profiles in peripheral blood from 206 vaccinated or unvaccinated adult subjects enrolled in the 2018 SHIVERS-II cohort to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza infection. Protection from symptomatic influenza correlated with increased individual frequencies of diverse and polyfunctional CD4 and CD8 T cells, cells associated with engagement of humoral responses including cTfh and mDCs, Th17 cells, and innate effector CD16-expressing cytotoxic and cytokine-producing NK cells. In contrast, increased susceptibility was predominantly attributed to nonspecific inflammatory populations including γδ T cells and activated CD16 neg NK cells, as well as TNFα + single-producing CD8 T cells. A trained random forest model categorizing symptomatic influenza cases identified that cellular covariates substantially improved model accuracy up to 86% over demographic and serologic factors alone (61%). A corresponding variable importance analysis showed cellular populations comprise 28 of the top 30 covariates (from 48 total), with the single most important factor being ICOS + cTfh cells. Lastly, using a multivariate logistic regression model considering participant demographics, anti-influenza antibody titers, vaccination status, and cell population covariates, we quantified how these factors contribute to risk of symptomatic influenza infection. Protection was associated with a combination of lymphocyte populations including naïve, CD107a + , and Th17 CD4 T cells, and serologic factors including antibodies targeting neuraminidase. Increased risk of symptomatic influenza (95% subtype A) was associated with elevated anti-hemagglutinin antibodies against influenza B (Yamagata), along with γδ T cells and TNFα + CD8 T cell single-cytokine producers. Together, these results demonstrate that the composition of pre-infection peripheral cell profiles is a stronger predictor of symptomatic influenza susceptibility than vaccination, demographics, or serology. Biological sciences/Immunology/Infectious diseases/Influenza virus Biological sciences/Immunology/Vaccines Biological sciences/Immunology/Adaptive immunity/Cellular immunity Biological sciences/Immunology/Innate immune cells Biological sciences/Immunology/Adaptive immunity/Humoral immunity Full Text Additional Declarations Yes there is potential Competing Interest. P.G.T. has consulted or received honorarium and/or travel support from Illumina, JNJ, Pfizer, and 10X. P.G.T. serves on the Scientific Advisory Board of ImmunoScape and CytoAgents. Supplementary Files SupplementFiguresandTables.pdf Cite Share Download PDF Status: Published Journal Publication published 17 Aug, 2023 Read the published version in Nature Immunology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2371124","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":165354882,"identity":"105a48a8-a106-4ff7-82b6-f799f4279fde","order_by":0,"name":"Paul 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P.G.T. serves on the Scientific Advisory Board of ImmunoScape and CytoAgents.","formattedTitle":"Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2371124/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2371124/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInfluenza viruses remain a leading cause of global respiratory illness in humans. The suboptimal effectiveness of seasonal influenza vaccination underscores the need for a more comprehensive understanding of immune mediators of protection, especially in populations with diverse baseline immune profiles and exposure histories. While anti-influenza antibody titers are typically used to define correlates of protection, mounting evidence suggests a substantive role for innate and cellular immunity in determining tolerance and resistance during influenza virus infection. However, distinct cell subsets that correlate with protection against symptomatic influenza remain to be identified in humans. Here, we measured baseline cellular and serologic profiles in peripheral blood from 206 vaccinated or unvaccinated adult subjects enrolled in the 2018 SHIVERS-II cohort to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza infection. Protection from symptomatic influenza correlated with increased individual frequencies of diverse and polyfunctional CD4 and CD8 T cells, cells associated with engagement of humoral responses including cTfh and mDCs, Th17 cells, and innate effector CD16-expressing cytotoxic and cytokine-producing NK cells. In contrast, increased susceptibility was predominantly attributed to nonspecific inflammatory populations including γδ T cells and activated CD16\u003csup\u003eneg\u003c/sup\u003e NK cells, as well as TNFα\u003csup\u003e+\u003c/sup\u003e single-producing CD8 T cells. A trained random forest model categorizing symptomatic influenza cases identified that cellular covariates substantially improved model accuracy up to 86% over demographic and serologic factors alone (61%). A corresponding variable importance analysis showed cellular populations comprise 28 of the top 30 covariates (from 48 total), with the single most important factor being ICOS\u003csup\u003e+\u003c/sup\u003e cTfh cells. Lastly, using a multivariate logistic regression model considering participant demographics, anti-influenza antibody titers, vaccination status, and cell population covariates, we quantified how these factors contribute to risk of symptomatic influenza infection. Protection was associated with a combination of lymphocyte populations including naïve, CD107a\u003csup\u003e+\u003c/sup\u003e, and Th17 CD4 T cells, and serologic factors including antibodies targeting neuraminidase. Increased risk of symptomatic influenza (95% subtype A) was associated with elevated anti-hemagglutinin antibodies against influenza B (Yamagata), along with γδ T cells and TNFα\u003csup\u003e+\u003c/sup\u003e CD8 T cell single-cytokine producers. Together, these results demonstrate that the composition of pre-infection peripheral cell profiles is a stronger predictor of symptomatic influenza susceptibility than vaccination, demographics, or serology.\u003c/p\u003e","manuscriptTitle":"Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-06 02:37:14","doi":"10.21203/rs.3.rs-2371124/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-immunology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ni","sideBox":"Learn more about [Nature Immunology](http://www.nature.com/ni/)","snPcode":"","submissionUrl":"","title":"Nature Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"afc0b6eb-835c-469e-835d-9bccbf4ee9dc","owner":[],"postedDate":"January 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":18182583,"name":"Biological sciences/Immunology/Infectious diseases/Influenza virus"},{"id":18182584,"name":"Biological sciences/Immunology/Vaccines"},{"id":18182585,"name":"Biological sciences/Immunology/Adaptive immunity/Cellular immunity"},{"id":18182586,"name":"Biological sciences/Immunology/Innate immune cells"},{"id":18182587,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity"}],"tags":[],"updatedAt":"2023-08-18T07:09:20+00:00","versionOfRecord":{"articleIdentity":"rs-2371124","link":"https://doi.org/10.1038/s41590-023-01590-2","journal":{"identity":"nature-immunology","isVorOnly":false,"title":"Nature Immunology"},"publishedOn":"2023-08-17 04:00:00","publishedOnDateReadable":"August 17th, 2023"},"versionCreatedAt":"2023-01-06 02:37:14","video":"","vorDoi":"10.1038/s41590-023-01590-2","vorDoiUrl":"https://doi.org/10.1038/s41590-023-01590-2","workflowStages":[]},"version":"v1","identity":"rs-2371124","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2371124","identity":"rs-2371124","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}