Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus

Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus | 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 Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus Deepak Rao, Takanori Sasaki, John Sowerby, Yinan Xiao, Runci Wang, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7472890/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate substantial clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5- PD-1hi) from SLE patients revealed considerable heterogeneity among these cells and highlighted a subpopulation of cells with transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression of TOX and CXCL13, was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in SLE. The persistence of expanded Tph and Tfh cells clones over time may explain the lack of stable tolerance induction by immunosuppressive medications or by B cell depletion. Biological sciences/Immunology/Autoimmunity Biological sciences/Immunology/Immunological disorders/Autoimmune diseases/Systemic lupus erythematosus Systemic lupus erythematosus T follicular helper cell T peripheral helper cell T cell receptor repertoire Full Text Additional Declarations Yes there is potential Competing Interest. The work was performed in part with grant support from Merck & Co., Inc. D.A.R. reports grant support from Janssen and Bristol-Myers Squibb outside of the current report, and reports personal fees from AstraZeneca, Pfizer, Merck, Abbvie, Simcere, Biogen, and Bristol-Myers Squibb. He is co-inventor on a patent using T peripheral helper cells as a biomarker of autoimmune diseases. Y.Q., M.A.S., S.E.A., and M.C.L. are employees of Merck & Co., Inc. Cite Share Download PDF Status: Posted 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-7472890","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":513289880,"identity":"2ff16c52-271b-469b-8e99-65f32e661f96","order_by":0,"name":"Deepak Rao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYDCCAyCi4gCDAQMPQkSCsJYzJGthbCNFC9/xsw8/fJx3J3E7A+/Bz5Vtdvl8B5gP3ubBo0XyTLqx5MxtzxJ3NvAlS55tS7aceYAt2RqfFoMDaQzSvNsO5244wGMg2XCG2cDgAI+ZNF4t558x/+adA9Zi/LPhTD1QC/83/FpupLFJ8zaAtZhJNlQcBtnChleL5I1nbJYzjj2r33CYx8yyoeK4geRhNmPLOXi08J1PY77xoeaOscHxHuObDQbVBnzHmx/eeINHCwIwYzBGwSgYBaNgFJANAKWSUxqKVQPeAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9672-7746","institution":"Brigham and Women's Hospital, Harvard Medical School","correspondingAuthor":true,"prefix":"","firstName":"Deepak","middleName":"","lastName":"Rao","suffix":""},{"id":513289881,"identity":"c3654c86-e77e-4ac6-95b8-44ac65105a61","order_by":1,"name":"Takanori Sasaki","email":"","orcid":"","institution":"Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA","correspondingAuthor":false,"prefix":"","firstName":"Takanori","middleName":"","lastName":"Sasaki","suffix":""},{"id":513289882,"identity":"0fa97c11-c5c9-4ed8-b62b-fd63d8ce416e","order_by":2,"name":"John Sowerby","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Sowerby","suffix":""},{"id":513289883,"identity":"79a198a1-6a18-4ddb-a247-d3e1bbfe3276","order_by":3,"name":"Yinan Xiao","email":"","orcid":"","institution":"Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA","correspondingAuthor":false,"prefix":"","firstName":"Yinan","middleName":"","lastName":"Xiao","suffix":""},{"id":513289884,"identity":"56ee565c-8b71-4240-8c8b-9ddd95652d91","order_by":4,"name":"Runci Wang","email":"","orcid":"https://orcid.org/0000-0001-9536-2845","institution":"Brigham and Women's Hospital and Harvard Medical School; 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D.A.R. reports grant support from Janssen and Bristol-Myers Squibb outside of the current report, and reports personal fees from AstraZeneca, Pfizer, Merck, Abbvie, Simcere, Biogen, and Bristol-Myers Squibb. He is co-inventor on a patent using T peripheral helper cells as a biomarker of autoimmune diseases. Y.Q., M.A.S., S.E.A., and M.C.L. are employees of Merck \u0026 Co., Inc.","formattedTitle":"Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Systemic lupus erythematosus, T follicular helper cell, T peripheral helper cell, T cell receptor repertoire","lastPublishedDoi":"10.21203/rs.3.rs-7472890/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7472890/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate substantial clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5- PD-1hi) from SLE patients revealed considerable heterogeneity among these cells and highlighted a subpopulation of cells with transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression of TOX and CXCL13, was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in SLE. The persistence of expanded Tph and Tfh cells clones over time may explain the lack of stable tolerance induction by immunosuppressive medications or by B cell depletion.","manuscriptTitle":"Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 02:33:35","doi":"10.21203/rs.3.rs-7472890/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b940e91-f611-4061-a6ed-be1caf7f04af","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54530763,"name":"Biological sciences/Immunology/Autoimmunity"},{"id":54530764,"name":"Biological sciences/Immunology/Immunological disorders/Autoimmune diseases/Systemic lupus erythematosus"}],"tags":[],"updatedAt":"2026-05-07T07:35:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 02:33:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7472890","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7472890","identity":"rs-7472890","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}