Sequential Lymphotoxin Beta Receptor and Retinoic Acid Receptor signals regulate cDC2 fates

Sequential Lymphotoxin Beta Receptor and Retinoic Acid Receptor signals regulate cDC2 fates | 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 Sequential Lymphotoxin Beta Receptor and Retinoic Acid Receptor signals regulate cDC2 fates Albert Nguyen, Logan Fisher, Jennifer Ahn, Michelle Zuo, Tyler Park, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4784425/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Nature Immunology → Version 2 posted You are reading this latest preprint version Show more versions Abstract Type II conventional dendritic cells (cDC2) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2A and cDC2B) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here we delineate murine cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+ cDC progenitor, encompass T-bet-expressing cDC2A and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3 exhibiting transcriptional overlap with Mgl2– cDC2B. Among these subsets, T-bet+ cDC2A dominate the spleen where they require cell-intrinsic retinoic acid (RA) signaling to sustain their differentiation via Notch signals. Lymphotoxin beta receptor signaling on splenic cDC2s limits F-actin content retaining cDC2 at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues. Biological sciences/Immunology Biological sciences/Immunology Biological sciences/Immunology/Innate immune cells Biological sciences/Immunology/Innate immune cells Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable2.csv Supplementary Table 2 SupplementaryTable1.csv Supplementary Table 1 Cite Share Download PDF Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Nature Immunology → Version 2 posted You are reading this latest preprint version Show more versions 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. 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fates","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 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Previous work in mice and humans identified two cDC2 subsets (cDC2A and cDC2B) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here we delineate murine cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+ cDC progenitor, encompass T-bet-expressing cDC2A and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3 exhibiting transcriptional overlap with Mgl2– cDC2B. Among these subsets, T-bet+ cDC2A dominate the spleen where they require cell-intrinsic retinoic acid (RA) signaling to sustain their differentiation via Notch signals. Lymphotoxin beta receptor signaling on splenic cDC2s limits F-actin content retaining cDC2 at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.","manuscriptTitle":"Sequential Lymphotoxin Beta Receptor and Retinoic Acid Receptor signals regulate cDC2 fates","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-10-16 14:36:24","doi":"10.21203/rs.3.rs-4784425/v2","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":"9fb4094c-516f-11e9-9e20-12b504df345a","owner":[],"postedDate":"October 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55919908,"name":"Biological sciences/Immunology"},{"id":55919909,"name":"Biological sciences/Immunology"},{"id":55919910,"name":"Biological sciences/Immunology/Innate immune cells"},{"id":55919911,"name":"Biological sciences/Immunology/Innate immune cells"}],"tags":[],"updatedAt":"2025-11-22T08:06:57+00:00","versionOfRecord":{"articleIdentity":"rs-4784425","link":"https://doi.org/10.1038/s41590-025-02329-x","journal":{"identity":"nature-immunology","isVorOnly":false,"title":"Nature Immunology"},"publishedOn":"2025-11-21 05:00:00","publishedOnDateReadable":"November 21st, 2025"},"versionCreatedAt":"2025-10-16 14:36:24","video":"","vorDoi":"10.1038/s41590-025-02329-x","vorDoiUrl":"https://doi.org/10.1038/s41590-025-02329-x","workflowStages":[]},"version":"v2","identity":"rs-4784425","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4784425","identity":"rs-4784425","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}