{"paper_id":"0106dddf-2d89-4d9b-9d59-1422f1640bf2","body_text":"Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control | 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 Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control Sheikh Rahman, Saleem Anwar, Sadek Naseem, Christian Beusch, Ahmet Coskun, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8824573/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Effective T cell reconstitution in people living with HIV is central to durable immune control and cure strategies. Sustained thymic output underpins T cell recovery and requires continuous seeding by T cell-committed progenitors originating in the bone marrow (BM). Using the SIV/rhesus macaque model, we identified a lymphoid thymus-seeding progenitor (TSP; CD4⁻CD8⁻CD34⁺CD38⁻CD7⁺) in BM that declined following SIV infection and closely associated with reduced T cell lineage biased differentiation of hematopoietic stem and progenitor cells (HSPCs). Importantly, both the decline in TSPs and the impairment of pre-thymic T cell potential were strongly associated with early loss of viral control, independent of peripheral T cell dynamics. Plasma interleukin-6 (IL-6) levels robustly predicted the magnitude of TSP loss and the restriction in T cell-biased HSPC differentiation. Transcriptomic and proteomic analyses revealed inflammatory imprinting of HSPCs characterized by activation of the IL-6-JAK-STAT axis, inflammasome engagement, and coordinated suppression of key T cell specification factors, including RUNX1, FYN, and ZAP70. In a nonanimal model of thymopoiesis, exposure of rhesus macaque or human HSPCs to IL-6 inhibited their transition from DN1 (CD38⁻) to DN2 (CD38⁺) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo blockade of IL-6 receptors restored thymocyte differentiation to levels comparable to that in untreated controls. Collectively, these findings demonstrate that pathogenic inflammation restricts pre-thymic T cell development early after infection, directly contributing to loss of viral control. These findings have important implications for understanding the mediators of anti-viral T cell immunity and HIV cure. Biological sciences/Immunology/Inflammation/Chronic inflammation Biological sciences/Stem cells/Stem-cell differentiation Biological sciences/Immunology/Infectious diseases/HIV infections Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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-8824573\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Biological Sciences - Article\",\"associatedPublications\":[],\"authors\":[{\"id\":590476557,\"identity\":\"b7209805-de64-49e4-9d25-9580574087e4\",\"order_by\":0,\"name\":\"Sheikh Rahman\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"https://orcid.org/0000-0002-3832-2713\",\"institution\":\"Emory University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Sheikh\",\"middleName\":\"\",\"lastName\":\"Rahman\",\"suffix\":\"\"},{\"id\":590476558,\"identity\":\"f639235c-3685-462f-8b1c-bde7ec23b881\",\"order_by\":1,\"name\":\"Saleem Anwar\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Emory University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Saleem\",\"middleName\":\"\",\"lastName\":\"Anwar\",\"suffix\":\"\"},{\"id\":590476559,\"identity\":\"46431d26-94e8-41ec-9451-bac2c37a4fdb\",\"order_by\":2,\"name\":\"Sadek Naseem\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Emory University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sadek\",\"middleName\":\"\",\"lastName\":\"Naseem\",\"suffix\":\"\"},{\"id\":590476560,\"identity\":\"e6f05564-0b1d-46d3-b0ff-ca2c24db0a85\",\"order_by\":3,\"name\":\"Christian Beusch\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0001-9100-8283\",\"institution\":\"Emory University School of Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Christian\",\"middleName\":\"\",\"lastName\":\"Beusch\",\"suffix\":\"\"},{\"id\":590476561,\"identity\":\"06bdd7f6-deed-4b15-bd1e-e45ef3a8d41b\",\"order_by\":4,\"name\":\"Ahmet Coskun\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-5797-1524\",\"institution\":\"Georgia Institute of Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ahmet\",\"middleName\":\"\",\"lastName\":\"Coskun\",\"suffix\":\"\"},{\"id\":590476562,\"identity\":\"37de3980-d828-424b-ac50-2a7fd36d64f6\",\"order_by\":5,\"name\":\"Daniel Kalman\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Emory University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Daniel\",\"middleName\":\"\",\"lastName\":\"Kalman\",\"suffix\":\"\"},{\"id\":590476563,\"identity\":\"aea072cd-3197-499d-9166-0a2758278eb4\",\"order_by\":6,\"name\":\"Mohamed Abdel-Hakeem\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0003-0226-3464\",\"institution\":\"Emory University School of Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mohamed\",\"middleName\":\"\",\"lastName\":\"Abdel-Hakeem\",\"suffix\":\"\"},{\"id\":590476564,\"identity\":\"c30e274a-4a5c-4877-872c-6b6fd5eb2408\",\"order_by\":7,\"name\":\"R. 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