Tlr7-biallelism defines a hyperfunctional state of female B lymphocytes

Tlr7-biallelism defines a hyperfunctional state of female B lymphocytes | 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 Tlr7-biallelism defines a hyperfunctional state of female B lymphocytes Jean Charles Guery, Charles-Henry Miquel, Mélissa Nieucel, Léa Ferrayé, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8306714/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 Enhanced dosage of the Toll-like receptor TLR7 is closely associated with sex disparities in systemic autoimmunity1-3. Remarkably, TLR7 escapes X chromosome inactivation in immune cells of women, leading to elevated protein levels4,5. However, the direct contribution of this process to immune cell function and systemic autoimmunity is unknown. Here, we use novel female Tlr7-reporter mice and identify a unique subset of mature B cells with bi-allelic Tlr7 expression (BiA7), with higher levels of TLR7 protein, poised for immediate differentiation into antibody secreting cells. We show that the epigenomic signature of BiA7 B cells resembles that of memory B cells, and that their development is independent of BCR self-reactivity or MyD88-signaling but is considerably boosted by type I IFN. Such BiA7 B cells accumulate in age-associated atypical memory B cell populations, which contribute to systemic autoimmunity. Accordingly, constitutive ablation of these cells protects mice from lupus development. Thus, Tlr7 expression from the inactive X chromosome characterizes a unique female-specific hyperactive subset of B lymphocytes and underlies systemic autoimmunity. Collectively, this study provides a mechanism to explain the X-linked genetic disparity in B cell immunity and supports future efforts to target X chromosome inactivation maintenance as a broad therapeutic strategy in sex-biased autoimmune disorders. Biological sciences/Immunology/Autoimmunity Health sciences/Pathogenesis/Immunopathogenesis/Adaptive immunity/Humoral immunity Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable4.pdf Supplementary Table 4 supplementarytable2DAR.xlsx Supplementary Table 2 supplementarytable3RNAseqactivatedBcells.xlsx Supplementary Table 3 SupplementaryTable1BiAvsMonoA.FC1.padj0.05.xlsx Supplementary Table 1 ExtendedDataFigure110.pdf Extended Data Figure 1 to Figure 10 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-8306714","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":557217181,"identity":"bf2fcdc9-53f1-44cf-9a89-8afee5056bad","order_by":0,"name":"Jean Charles 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Remarkably, TLR7 escapes X chromosome inactivation in immune cells of women, leading to elevated protein levels4,5. However, the direct contribution of this process to immune cell function and systemic autoimmunity is unknown. Here, we use novel female Tlr7-reporter mice and identify a unique subset of mature B cells with bi-allelic Tlr7 expression (BiA7), with higher levels of TLR7 protein, poised for immediate differentiation into antibody secreting cells. We show that the epigenomic signature of BiA7 B cells resembles that of memory B cells, and that their development is independent of BCR self-reactivity or MyD88-signaling but is considerably boosted by type I IFN. Such BiA7 B cells accumulate in age-associated atypical memory B cell populations, which contribute to systemic autoimmunity. Accordingly, constitutive ablation of these cells protects mice from lupus development. 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