The origins of IgA-secreting cells in the acinar structures of the nasal turbinates

The origins of IgA-secreting cells in the acinar structures of the nasal turbinates | 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 The origins of IgA-secreting cells in the acinar structures of the nasal turbinates Ziv Shulman, Jingjing Liu, Liat Stoler-Barak, Hadas Hezroni-Bravyi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3690682/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways remain unknown. Here, we define glandular acinus structures of the nasal turbinates as an immunological niche that recruits IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALT) in response to intranasal vaccination. Using intact organ imaging to visualize cognate T and B cells in the upper airways, we demonstrate that nasal vaccination induced extensive B cell expansion in the subepithelial dome (SED) of the NALT, followed by invasion into commensal bacteria-driven chronic germinal centers (GCs) in a T cell-dependent manner. Antigen-specific B cell response in the NALT required pre-expansion of cognate T cells, which initiate the immune response in the inter-follicular regions of the NALT, and occurred effectively in the presence of Monophosphoryl-Lipid A (MPLA), a synthetic, non-toxic TLR-4 agonist. NALT ablation and blockade of PSGL-1 demonstrated that intranasal vaccination generates IgA-expressing plasma cells that home to the nasal turbinates through the blood circulation where they are positioned primarily around glandular acinus structures. Thus, the glandular part of the nasal turbinate is an immunological niche that hosts NALT-derived IgA-secreting cells. These cellular events can be manipulated to design vaccines against inhaled pathogens or in the treatment of upper airway allergic responses. Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Germinal centres Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files tables.xlsx Table s1 and s2 Video1.mp4 Extended Data Video 1 Video2.mp4 Extended Data Video 2 Video3.mp4 Extended Data Video 3 ExtendedDataFigure1.pdf Extended Data Figure 1 ExtendedDataFigure2.pdf Extended Data Figure 2 ExtendedDataFigure3.pdf Extended Data Figure 3 ExtendedDataFigure4.pdf Extended Data Figure 4 ExtendedDataFigure5.pdf Extended Data Figure 5 Extendeddata.pdf Extended Data Figures Cite Share Download PDF Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Nature → 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. 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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-3690682","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":255180346,"identity":"1c8650ed-cc0e-4074-a54f-74c39eb20562","order_by":0,"name":"Ziv 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LNs were derived from WT mice injected with naïve GFP+ B cells and naïve Rosa26tdTomato/+ CD4+ T cells, and imaged by TPLSM one day after cell transferring. Scale bars, 300μm. n=2. (B) Flow cytometry analysis of the ratio between CD4+ T cells and B220+ B cells in the NALT and MedLN. LNs were collected from naïve mice. n=6; 3 independent experiments. (C) Experimental design for (D-G). (D) Representative TPLSM images of NALT-derived from AID-GFP+ host mice that were adoptively transferred with Rosa26tdTomato/+ B1-8hi B cells and CD4+ OT-II T cells, and imaged by TPLSM at day 5 and day 10 post NP-OVA+MPLA i.n. Scale bars, 300μm. n=6; 3 independent experiments. (E) NALT were derived from CD11c-YFP+ host mice adoptively injected with GFP+ B1-8hi B\u003c/p\u003e\n\u003cp\u003ecells and with Rosa26tdTomato/+ CD4+ OT-II T cells, and imaged by TPLSM at day 5 and day 10 following i.n. NP-OVA+MPLA. Scale bars, 300μm; zoom in, 30μm. n=4; 2 independent experiments. (F, G) NALT and MedLN were derived from WT host mice adoptively injected with GFP+ B1-8hi B cells and Rosa26tdTomato/+ CD4+ OT-II T cells, and imaged by TPLSM at different days following i.n. NP-OVA+MPLA. Scale bars, (F), 50-300μm; (G), 500μm. n=3-8; 8 independent experiments. (H) Flow Cytometry analysis of NALT and MedLN at day 5, and day 7 to 10 following i.n. NP-OVA + MPLA. IgA+ or IgG1+ population was gated from the GFP+ B220+ CD138- B1-8hi B cell compartment. n=6-11; data from 4 independent experiments. (I) Single-cell RNA-seq of sorted GFP+ B1-8hi B cells in the NALT and MedLN 5 days after i.n. NP-OVA+MPLA. UMAP projections of scRNA-seq profiles of 2,028 cells from the NALTs and 2,835 cells from the MedLNs. Clusters in the UMAP plots are color-coded according to different cell populations. Data was pooled from 5 mice.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3690682/v1/b1cec2f6cba9e1b448585c7e.jpg"},{"id":48288997,"identity":"7837db03-2378-45a0-a010-451c241eb279","added_by":"auto","created_at":"2023-12-15 17:05:29","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":906275,"visible":true,"origin":"","legend":"\u003cp\u003eGerminal center formation in the NALT depends on pre-expansion of CD4+ T cells.\u003c/p\u003e\n\u003cp\u003e(A) Representative TPLSM images of NALT at different time points following i.n. NPOVA+ MPLA. NALT derived from AID-GFP+ host mice adoptively injected with Rosa26tdTomato/+ CD4+ OT-II T cells, were imaged at different days following i.n. NP-OVA+MPLA immunization. Scale bars, 300μm; zoom in, 70μm. n=5. (B) Representative FACS plots and quantification of Tfh cells in the NALT derived from WT host mice that were adoptively transferred with GFP+ B1-8hi B cells and Rosa26tdTomato/+ CD4+ OT-II T cells and analyzed on days 5 or 7 following i.n. NP-OVA+MPLA. PD1+ CXCR5+ population gated from the CD62L- CD4+ CD45+ OT-II T cell compartment. n=8-11; 4 independent experiments. (C) Representative flow cytometry plots and quantification of Tfh cells in the NALT derived from WT host mice that were adoptively transferred with MHC-II WT (I-Ab+/+) or MHC-II KO (I-Ab-/- ) Rosa26tdTomato/+ B1-8hi B cells and GFP+ CD4+ OT-II T cells 5 days following immunization with NP-OVA+MPLA. PD1+ CXCR5+population gated from CD62L- CD4+ CD45+ OT-II T cell compartment. n=6; 2 independent experiments. (D, E) WT host mice were adoptively transferred with GFP+ B1-8hi B cells, with or without the addition of Rosa26tdTomato/+ CD4+ OT-II T cells. (D) Representative plots and quantification of NALT (left) and MedLN (right) at day 7 following i.n. NP-OVA+MPLA. B1- 8hi population gated from the FAS+ CD38- GC compartment. n=6, 2 independent experiments. (E) Representative TPLMS images of NALT and MedLN on day 7 following i.n. NP-OVA+MPLA. Scale bars, 200μm - 500μm. n=6, 2 independent experiments. (F) Representative flow cytometry plots and quantification of B1-8hi cells in the NALT and MedLN. LNs derived from WT host mice that were adoptively transferred with MHC-II WT (I-Ab+/+) or MHC-II KO (I-Ab-/-) Rosa26tdTomato/+ B1-8hi B cells mixed with GFP+ CD4+ OT-II T cells and analyzed at 5 days following i.n. NP-OVA+MPLA. B1-8hi B220+ population gated from CD45+ compartment. n=6; 2 independent experiments. (G) Experimental design for (H). (H) Flow cytometry quantification of B cells in NALT at day 7 following NP-OVA intranasal boost. GFP+ B1-8hi B cell population gated from FAS+ CD38- B220+ GC compartment. n= 6-12; 4 independent experiments.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3690682/v1/f408e59f915b84067c999fd5.jpg"},{"id":48288999,"identity":"27827e69-ad8f-4a51-8364-354b5c8e0864","added_by":"auto","created_at":"2023-12-15 17:05:29","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1044083,"visible":true,"origin":"","legend":"\u003cp\u003eAntigen-specific B cells are recruited to the nasal turbinate in response to nasal vaccination.\u003c/p\u003e\n\u003cp\u003e(A) Representative TPLMS images of antigen-specific plasma cells in the NALT and MedLN at day 7 post i.n. NP-OVA+MPLA boost. LNs derived from WT host mice that were adoptively transferred with Blimp1-YFP Rosa26tdTomato/+ B1-8hi B cells and CD4+ OT-II T cells following i.n. NP-OVA+MPLA prime (d0) and boost (d14). Scale bars, 200μm. n= 10; 2 independent experiments. (B) Sagittal section of the nasal cavity of a naïve WT mouse by H\u0026amp;E staining. Scale bars, 1000μm. (C) Representative digital slide scanner and confocal images of GFP+ B1-8hi B cells located in the NT. WT host mice were adoptively transferred with GFP+ B1-8hi B cells and CD4+ OT-II T cells following prime and boost vaccination. The upper heads were collected at 7 days post boost. Scale bars, 50μm. (D) Flow cytometry quantification of GFP+ B1-8hi B cells in NT and BM at day 7 following NP-OVA intranasal boost. n=7-14; 4 independent experiments. (E) Representative confocal images and flow cytometry quantification of B1-8hi B cells in the NT. WT host mice were adoptively transferred with Blimp1-YFP Rosa26tdTomato/+ B1-8hi B cells and CD4+ OT-II T cells following i.n. NP-OVA+MPLA prime and boost vaccination. Upper mouse\u003c/p\u003e\n\u003cp\u003eheads were collected 7 days following boost. Scale bars, 50μm. Blimp1-YFP+ population gated from Rosa26tdTomato/+ B1-8hi B cell compartment. n=5; 2 independent experiments. (F) Representative plots and quantification of IgA+ B1-8hi B cells in the NT. IgA+ population gated from the Blimp1-YFP+ Rosa26tdTomato/+ B1-8hi B cell compartment (D). n=5; 2 independent experiments. (G) Representative confocal images of the NT after several vaccine strategies. i.n.: i.n. NP-OVA+MPLA prime and boost; i.p.+s.c.: NP-OVA+Alum i.p. prime and s.c. NPOVA+ MPLA boost; oral gavage with NP-CT. (27/38): NT-homing GFP+ B1-8hi B cells were detected in 27 out of 38 experimental mice. (H) H\u0026amp;E staining and confocal imaging showing the B cells localized in lamina propria of the NT of unimmunized mice. Representative confocal images and quantification of the Blimp1-YFP+ cells out of AicdaCre/+ Rosa26Stop-tdTomato/+ B cells of the NT from naïve mice. The ratio of Blimp1-YFP+/AicdaCre/+ Rosa26Stop-tdTomato/+ B cells was calculated by Imaris software. n=19.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3690682/v1/61bf9c7657327d43ab2af780.jpg"},{"id":48289002,"identity":"23105419-70f8-47a4-babc-464b2707f807","added_by":"auto","created_at":"2023-12-15 17:05:29","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":872602,"visible":true,"origin":"","legend":"\u003cp\u003eNasal turbinate-homing B cells are generated in the NALT.\u003c/p\u003e\n\u003cp\u003e(A) Representative TPLMS images of the NALTs with or without a GC response, and confocal images of the NT at 7 days following i.n. NP-OVA+MPLA boost. n=20; 4 independent experiments. 14 mice exhibited a NALT GC response out of 20 tested. (B) Flow cytometry plots and quantification of GFP+ B1-8hi B cell number in the NT with or without NALT GC response. n=7-9; 4 independent experiments. (C) Representative TPLMS images of the NALT and MedLN, and confocal images of the NT at 7-days following i.n. NP-OVA+MPLA boost. Sham: surgery without NALT ablation; Ablation: surgery-damaging NALT. 4 mice detected NT-homing GFP+ B1-8hi B cell out of 4 tested. (D) Flow cytometry plots and ratios of the GFP+ B1-8hi B cells vs counting beads in the NT from the Sham or Ablation groups. n=5. (E) Flow cytometry plots and quantification of the PSGL-1 expressing B1-8hi B cell. BM and NT collected at 7-days post i.n. NP-OVA+MPLA boost. PSGL-1 population gated from GFP+ B1-8hi B cells. n=7-10; data from 3 independent experiments. (F) Representative TPLMS images of the NALT and confocal images of the NT at 7-days post i.n. NP-OVA+MPLA boost, with or without anti-PSGL1 injection. 5 mice detected NT-homing GFP+ B1-8hi B cell out of 7 tested. (G) Flow cytometry plots and quantification of (F). n=3-6; 2 independent experiments.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3690682/v1/7ce5e65cd88e529e9b0271a8.jpg"},{"id":61554759,"identity":"d8dda63f-e24f-4bec-8e9a-6c4388faaf84","added_by":"auto","created_at":"2024-08-01 07:17:04","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4210464,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Maintext2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3690682/v1_covered_ae5429f0-473b-4225-9c15-8dca71cbef74.pdf"},{"id":48288996,"identity":"51fa1292-f150-4d24-9df7-9c04a8e0e031","added_by":"auto","created_at":"2023-12-15 17:05:29","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13962,"visible":true,"origin":"","legend":"\u003cp\u003eTable s1 and 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turbinates","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-3690682/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3690682/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways remain unknown. Here, we define glandular acinus structures of the nasal turbinates as an immunological niche that recruits IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALT) in response to intranasal vaccination. Using intact organ imaging to visualize cognate T and B cells in the upper airways, we demonstrate that nasal vaccination induced extensive B cell expansion in the subepithelial dome (SED) of the NALT, followed by invasion into commensal bacteria-driven chronic germinal centers (GCs) in a T cell-dependent manner. Antigen-specific B cell response in the NALT required pre-expansion of cognate T cells, which initiate the immune response in the inter-follicular regions of the NALT, and occurred effectively in the presence of Monophosphoryl-Lipid A (MPLA), a synthetic, non-toxic TLR-4 agonist. NALT ablation and blockade of PSGL-1 demonstrated that intranasal vaccination generates IgA-expressing plasma cells that home to the nasal turbinates through the blood circulation where they are positioned primarily around glandular acinus structures. Thus, the glandular part of the nasal turbinate is an immunological niche that hosts NALT-derived IgA-secreting cells. These cellular events can be manipulated to design vaccines against inhaled pathogens or in the treatment of upper airway allergic responses.","manuscriptTitle":"The origins of IgA-secreting cells in the acinar structures of the nasal turbinates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-15 17:05:24","doi":"10.21203/rs.3.rs-3690682/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"619e4c43-203a-4b2f-8a7c-7241c29756c6","owner":[],"postedDate":"December 15th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":26957090,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Germinal centres"},{"id":26957091,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies"}],"tags":[],"updatedAt":"2024-08-01T07:16:56+00:00","versionOfRecord":{"articleIdentity":"rs-3690682","link":"https://doi.org/10.1038/s41586-024-07729-x","journal":{"identity":"nature","isVorOnly":false,"title":"Nature"},"publishedOn":"2024-07-31 04:00:00","publishedOnDateReadable":"July 31st, 2024"},"versionCreatedAt":"2023-12-15 17:05:24","video":"","vorDoi":"10.1038/s41586-024-07729-x","vorDoiUrl":"https://doi.org/10.1038/s41586-024-07729-x","workflowStages":[]},"version":"v1","identity":"rs-3690682","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3690682","identity":"rs-3690682","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}