Temporal and Context-Dependent Requirements for the Transcription Factor Foxp3 Expression in Regulatory T Cells

Temporal and Context-Dependent Requirements for the Transcription Factor Foxp3 Expression in Regulatory T Cells | 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 Temporal and Context-Dependent Requirements for the Transcription Factor Foxp3 Expression in Regulatory T Cells Alexander Rudensky, Wei Hu, Gabriel Dolsten, Giorgi Beroshvili, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6596747/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Oct, 2025 Read the published version in Nature Immunology → Version 1 posted You are reading this latest preprint version Abstract Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of the immune responsiveness. While Foxp3 essential role in Treg l differentiation is well established, the mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic system of inducible, time-controlled degradation of Foxp3 protein in vivo to dissect its Treg stage stage-specific functions. While Foxp3 was indispensable for the establishment of the Treg transcriptional program and suppressive function during thymic Treg progenitors and newly generated peripheral Treg cells, degradation of Foxp3 in mature Treg cells resulted in unexpectedly minimal transcriptional changes largely limited to direct Foxp3 targets and largely preserved suppressive capacity. However, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impaired suppressive function and tumor growth restraint absent pronounced adverse effects. These studies demonstrate context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs. Biological sciences/Immunology/Adaptive immunity/Immune tolerance Biological sciences/Immunology/Gene regulation in immune cells Full Text Additional Declarations Yes there is potential Competing Interest. A.Y.R. is an SAB member and has equity in Sonoma Biotherapeutics, RAPT Therapeutics, Coherus BioSciences, Santa Ana Bio, Odyssey Therapeutics, Nilo Therapeutics, and Vedanta Biosciences; he is also an SAB member of BioInvent and Amgen and a co-inventor of a CCR8+ Treg cell depletion IP licensed to Takeda, which is unrelated to the content of this publication. The remaining authors declare no competing interests. Z.-M. W. is an employee of Genentech Inc., which is unrelated to the content of this publication. Cite Share Download PDF Status: Published Journal Publication published 08 Oct, 2025 Read the published version in Nature Immunology → 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-6596747","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":455493294,"identity":"901243e3-1888-43a2-a1b9-58b62639bd4c","order_by":0,"name":"Alexander 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