Heterogeneity and plasticity of the naïve CD4+ T cell compartment

Heterogeneity and plasticity of the naïve CD4+ T cell compartment | 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 Heterogeneity and plasticity of the naïve CD4 + T cell compartment J. Louise Lines, Alia Sajani, Evelien Schaafsma, Walburga Croteau, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5744327/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 While naïve CD4+ T cells have historically been considered a homogenous population, recent studies have provided evidence that functional heterogeneity exists within this population. Using single cell RNA sequencing (scRNAseq), we identify five transcriptionally distinct naïve CD4+ T cell subsets that emerge within the single positive stage in the thymus: a quiescence cluster (TQ), a memory-like cluster (TMEM), a TCR reactive cluster (TTCR), an IFN responsive cluster (TIFN), and an undifferentiated cluster (TUND). Elevated expression of transcription factors KLF2, Mx1, and Nur77 within the TQ, TIFN, and TMEM clusters, respectively, allowed enrichment of these subsets for further analyses. Functional studies using sorted cells revealed that naïve T cell subsets have distinctive functional biases upon stimulation. Furthermore, treatment of mice with inflammatory stimuli imparted a state of reduced responsiveness on naïve T cells, evidenced by a reduction in cytokine production ex vivo. In human lupus patients, naïve CD4+ T cell cluster frequencies were distorted, with the TIFN cluster expanding proportionately with disease score. Our data show that naïve T cells are influenced by host environment, with functional consequences manifesting upon activation. These findings highlight a need to explore how naïve T cells can become distorted in cancer, autoimmunity, and infectious diseases. Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Lymphocyte differentiation Biological sciences/Immunology/Inflammation Naïve T cell heterogeneity scRNAseq IFN tonic signaling Full Text Additional Declarations There is NO Competing Interest. Supplementary Files PDFSupplementalFiguresTablesnatcomms.pdf Supplementary Dataset 1 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-5744327","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":400155816,"identity":"a27cd7e7-064f-4131-8033-1320c00cc571","order_by":0,"name":"J. 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Using single cell RNA sequencing (scRNAseq), we identify five transcriptionally distinct naïve CD4+ T cell subsets that emerge within the single positive stage in the thymus: a quiescence cluster (TQ), a memory-like cluster (TMEM), a TCR reactive cluster (TTCR), an IFN responsive cluster (TIFN), and an undifferentiated cluster (TUND). Elevated expression of transcription factors KLF2, Mx1, and Nur77 within the TQ, TIFN, and TMEM clusters, respectively, allowed enrichment of these subsets for further analyses. Functional studies using sorted cells revealed that naïve T cell subsets have distinctive functional biases upon stimulation. Furthermore, treatment of mice with inflammatory stimuli imparted a state of reduced responsiveness on naïve T cells, evidenced by a reduction in cytokine production ex vivo. In human lupus patients, naïve CD4+ T cell cluster frequencies were distorted, with the TIFN cluster expanding proportionately with disease score. 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