Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas

Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas | 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 Biological Sciences - Article Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas Emma Kuan, Nicholas Moss, Catalina Sakai, Saransh Kaul, Lucas Graybuck, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8197575/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Interferons (IFNs) orchestrate diverse immune responses, but distinguishing individual IFN contributions in human transcriptomic data is challenging due to overlapping interferon-stimulated gene (ISG) signatures and limited cell-type-specific datasets. To address this, we generated a single-cell transcriptomic atlas of IFN responses by stimulating primary human T, B, NK, and CD14 monocytes with IFN-I, IFN-II, and IFN-III. This revealed core and cell-type-specific ISG programs across 13 subsets, highlighting distinct functions of IFNs. We developed an algorithm to separate IFN-I and IFN-II activity in transcriptomic data. Applied to multiple myeloma samples, it showed elevated IFN-I and IFN-II responses, with induction therapy reducing only IFN-I. Extending to multiple disease datasets provided a cross-disease overview of IFN-I and IFN-II activities and revealed increased IFN-II activities in T cells during lupus flares. This resource and the accompanying analytical framework enable dissection of IFN-driven transcriptional programs in a cell-type specific manner in human disease. Biological sciences/Computational biology and bioinformatics/Databases/Genetic databases Biological sciences/Immunology/Cytokines/Interferons Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS8.csv Overlap or unique IFN-γ genes in GO Biological Process pathway TableS10.csv Shared or unique IFN-γ DEGs within T cell subsets TableS9.csv Shared or unique IFN-γ DEGs in memory, naive B cells, and plasma cells TableS2.csv IFN gene list, and their Log2FC and p-value in L2 subsets TableS11.csv Shared or unique IFN-α and IFN-γ induced DEG numbers in L2 TableS6.xlsx Stats results for Fig 2g TableS5.xlsx Stats results for Fig 2f TableS13.xlsx List of IFN-II specific DEGs in each immune cell subset TableS16.xlsx Information of antibodies used for flow cytometric assay in Fig. 3e TableS4.csv Overlap or unique IFN-α genes in GO Biological Process pathway TableS1.csv IFN gene list, and their Log2FC and p-value in L1 subsets TableS7.xlsx IFN-γ induced DEGs shared or unique in L1 immune subsets TableS15.xlsx Published scRNAseq datasets in various disease cohorts in Figure 5 TableS12.xlsx List of IFN-I specific DEGs in each immune cell subset TableS3.xlsx IFN-α induced DEGs shared or unique in L1 immune subsets TableS14.xlsx Timeline of cycle 1 and 2 induction therapy drugs in NDMM Cite Share Download PDF Status: Under Review 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8197575","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":558747927,"identity":"1e686b46-8efa-467f-bf19-c24edcdc38c6","order_by":0,"name":"Emma 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atlas","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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 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To address this, we generated a single-cell transcriptomic atlas of IFN responses by stimulating primary human T, B, NK, and CD14 monocytes with IFN-I, IFN-II, and IFN-III. This revealed core and cell-type-specific ISG programs across 13 subsets, highlighting distinct functions of IFNs. We developed an algorithm to separate IFN-I and IFN-II activity in transcriptomic data. Applied to multiple myeloma samples, it showed elevated IFN-I and IFN-II responses, with induction therapy reducing only IFN-I. Extending to multiple disease datasets provided a cross-disease overview of IFN-I and IFN-II activities and revealed increased IFN-II activities in T cells during lupus flares. This resource and the accompanying analytical framework enable dissection of IFN-driven transcriptional programs in a cell-type specific manner in human disease.","manuscriptTitle":"Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-23 04:46:57","doi":"10.21203/rs.3.rs-8197575/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8fa5cbf3-9c33-4f4d-a15b-e2cc7eeb7007","owner":[],"postedDate":"December 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59480445,"name":"Biological sciences/Computational biology and bioinformatics/Databases/Genetic databases"},{"id":59480446,"name":"Biological sciences/Immunology/Cytokines/Interferons"}],"tags":[],"updatedAt":"2025-12-23T04:46:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-23 04:46:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8197575","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8197575","identity":"rs-8197575","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}