Neonatal BCG Vaccination Engages the Vasculature to Elicit γδ T Cell–Mediated Protec-tion against Tuberculosis

Neonatal BCG Vaccination Engages the Vasculature to Elicit γδ T Cell–Mediated Protec-tion against Tuberculosis | 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 Neonatal BCG Vaccination Engages the Vasculature to Elicit γδ T Cell–Mediated Protec-tion against Tuberculosis Maziar Divangahi, Mina Sadeghi, Nargis Khan, Yao Chen, Leonardo Jurado, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8158832/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 The Bacillus Calmette–Guérin (BCG) vaccine remains the only approved vaccine against tuberculosis (TB). Although its efficacy against pulmonary TB in adults is limited, BCG provides remarkable protection against miliary TB when administered during infancy. Despite more than 100 million infants worldwide receiving BCG annually, the mechanisms underlying its neonatal protective effects remain poorly defined. Here, we demonstrate that subcutaneous neonatal BCG vaccination (BCG-sc) induces a marked expansion of γδ T cells producing IL-17 and IL-22, which mediated protection against subsequent Mycobacterium tuberculosis (Mtb) experimental infection. A similar expansion of γδ T cells was observed in a longitudinal cohort of infants, from birth to three months of infants followed after intradermal BCG vaccination. Mechanistically, BCG-mediated protection in neonates was linked to its early vascular dissemination through the distinct structure of neonatal skin, resembling the protective effects of intravenous BCG in adults. Moreover, neonatal BCG-sc vaccination generated a distinct BCG-induced microbiome signature, characterized by enrichment of Prevotellaceae, Tannerellaceae, and Bifidobacteriaceae, which was associated with protection. Together, these findings identify γδ T cells as key mediators of early-life BCG-induced immunity and highlight the role of the gut–lung axis in long-term protection against TB from infancy into adulthood. Biological sciences/Immunology/Vaccines/Live attenuated vaccines Biological sciences/Immunology/Infectious diseases/Tuberculosis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS1.xls Supplementary Table 1: List of differentially expressed genes in total, type 1 and type 2 γδ T cells from infants at 3 months of age. SuppFig1.pdf Supplementary Figure 1: Flow cytometry gating strategies for the evaluation of immune cells in the lungs of adult mice. SuppVideo1.mp4 Supplementary Video 1: Neonatal skin consists of intricate networks of small vessels with many intravascular BCG colonies. SuppVideo2.mp4 Supplementary Video 2: Adult skin sections display large vessels with rare intravascular BCG colonies. SuppVideo3.mp4 Supplementary Video 3: Adult skin contains a vasculature-adjacent adipose tissue layer which entraps BCG. 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-8158832","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":559404748,"identity":"5a424bc2-ca33-4da6-8e39-7c4bfb6bed6e","order_by":0,"name":"Maziar 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Although its efficacy against pulmonary TB in adults is limited, BCG provides remarkable protection against miliary TB when administered during infancy. Despite more than 100 million infants worldwide receiving BCG annually, the mechanisms underlying its neonatal protective effects remain poorly defined. Here, we demonstrate that subcutaneous neonatal BCG vaccination (BCG-sc) induces a marked expansion of γδ T cells producing IL-17 and IL-22, which mediated protection against subsequent Mycobacterium tuberculosis (Mtb) experimental infection. A similar expansion of γδ T cells was observed in a longitudinal cohort of infants, from birth to three months of infants followed after intradermal BCG vaccination. Mechanistically, BCG-mediated protection in neonates was linked to its early vascular dissemination through the distinct structure of neonatal skin, resembling the protective effects of intravenous BCG in adults. 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