{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:47:45Z","timestamp":1785433665080,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,2]]},"group-title":"Immunology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["OD035572"],"award-info":[{"award-number":["OD035572"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30AI050409"],"award-info":[{"award-number":["P30AI050409"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["OD011132"],"award-info":[{"award-number":["OD011132"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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 thymus-seeding progenitor (TSP; CD4\u207bCD8\u207bCD34\u207aCD38\u207bCD7\u207a) in BM declining rapidly following SIV infection. This loss closely associated with reduction in T cell lineage committed differentiation of BM-derived 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 of T cell-biased HSPC differentiation. Integrated 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, IL-6 exposure of rhesus macaque and human HSPCs inhibited their transition from DN1 (CD38\u207b) to DN2 (CD38\u207a) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo IL-6 receptor blockade restored thymocyte differentiation to levels comparable to 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.<\/jats:p>","DOI":"10.64898\/2026.01.29.702123","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:40:24Z","timestamp":1770061224000},"source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control"],"prefix":"10.64898","author":[{"given":"Saleem","family":"Anwar","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseem","family":"Sadek","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian Michel","family":"Beusch","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Surgical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-1524","authenticated-orcid":false,"given":"Ahmet F.","family":"Coskun","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA"},{"name":"Winship Cancer Institute, Emory University, Atlanta, GA, USA"},{"name":"Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-3464","authenticated-orcid":false,"given":"Mohamed S.","family":"Abdel-Hakeem","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and 9 Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA"},{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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