Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance

Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance | 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 Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance Alessandro Alessandrini, Koki Hayashi, Takahiro Yokose, Jenna Lancey, and 29 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7236564/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 We previously showed that infiltrating cytotoxic immune cells are reprogrammed to regulatory-like/exhausted cells within accepted kidney allografts through a ‘defensive tolerance’ mechanism. We observed a regulatory B cell (Breg) signature within the accepted kidney. Here we show that despite a Breg phenotype, neither B cell depletion nor the use of μMT recipients which lack B cells, resulted in kidney allograft rejection. Negative regulators of B cell function, Siglecg and Fcgr2b, show increased expression in both accepted kidney and lung allografts. Kidney allografts transplanted in B6.Fcgr2b KO recipients underwent antibody mediated rejection. Hypothesizing that similar mechanisms in a tumor microenvironment may attenuate anti-tumor immunity, we observed that expression of SIGLEC10, the human homolog of Siglecg, was associated with resistance to anti-PD1 therapy in human melanomas. In conclusion, B cell expression of FcγRIIB and Siglec-G appear to play an essential role in maintaining transplant tolerance and in tumor evasion of anti-tumor immunity. Biological sciences/Immunology/Transplant immunology Biological sciences/Immunology/Tumour immunology Biological sciences/Immunology/Adaptive immunity/Humoral immunity Full Text Additional Declarations Yes there is potential Competing Interest. GMB has sponsored research agreements through her institution with: Olink Proteomics, Teiko Bio, InterVenn Biosciences, Palleon Pharmaceuticals. She served on advisory boards for: Iovance, Merck, Moderna, Nektar Therapeutics, Novartis, Replimune, and Ankyra Therapeutics. She consults for: Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. JCM holds equity in Regatta Bio. 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. 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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-7236564","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":493975514,"identity":"f090d302-4ed7-4762-917f-879c0e63b110","order_by":0,"name":"Alessandro 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research agreements through her institution with: Olink Proteomics, Teiko Bio, InterVenn Biosciences, Palleon Pharmaceuticals. She served on advisory boards for: Iovance, Merck, Moderna, Nektar Therapeutics, Novartis, Replimune, and Ankyra Therapeutics. She consults for: Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. JCM holds equity in Regatta Bio.","formattedTitle":"Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance","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 Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7236564/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7236564/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"We previously showed that infiltrating cytotoxic immune cells are reprogrammed to regulatory-like/exhausted cells within accepted kidney allografts through a ‘defensive tolerance’ mechanism. We observed a regulatory B cell (Breg) signature within the accepted kidney. Here we show that despite a Breg phenotype, neither B cell depletion nor the use of μMT recipients which lack B cells, resulted in kidney allograft rejection. Negative regulators of B cell function, Siglecg and Fcgr2b, show increased expression in both accepted kidney and lung allografts. Kidney allografts transplanted in B6.Fcgr2b KO recipients underwent antibody mediated rejection. Hypothesizing that similar mechanisms in a tumor microenvironment may attenuate anti-tumor immunity, we observed that expression of SIGLEC10, the human homolog of Siglecg, was associated with resistance to anti-PD1 therapy in human melanomas. In conclusion, B cell expression of FcγRIIB and Siglec-G appear to play an essential role in maintaining transplant tolerance and in tumor evasion of anti-tumor immunity.","manuscriptTitle":"Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-18 16:50:03","doi":"10.21203/rs.3.rs-7236564/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":"d81da2a1-6ae4-4c0a-8571-b12e16f7d7af","owner":[],"postedDate":"August 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52462674,"name":"Biological sciences/Immunology/Transplant immunology"},{"id":52462675,"name":"Biological sciences/Immunology/Tumour immunology"},{"id":52462676,"name":"Biological sciences/Immunology/Adaptive immunity/Humoral immunity"}],"tags":[],"updatedAt":"2025-08-18T16:50:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-18 16:50:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7236564","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7236564","identity":"rs-7236564","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}