Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
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 thymus-seeding progenitor (TSP; CD4⁻CD8⁻CD34⁺CD38⁻CD7⁺) 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⁻) to DN2 (CD38⁺) 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.
Authors 13
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Emory University · Emory National Primate Research Center
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
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Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Uppsala University · Emory University
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Georgia Institute of Technology · Emory University · The Wallace H. Coulter Department of Biomedical Engineering · Winship Cancer Institute
Affiliation as printed
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
Winship Cancer Institute, Emory University, Atlanta, GA, USA
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Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA
Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and 9 Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
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Emory University · Emory National Primate Research Center
Affiliation as printed
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
Infectious Disease Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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Frank J. T. Staal Aachen Department of Immunology, Leiden University Medical Center Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Netherlands
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Emory University · Emory National Primate Research Center
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
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Emory University · Emory National Primate Research Center
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
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Frederick National Laboratory for Cancer Research
Affiliation as printed
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
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Emory University · Emory National Primate Research Center
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
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Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Sheikh Abdul Rahman corresponding
Emory University · Emory National Primate Research Center
Affiliation as printed
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Division of Microbiology and Immunology, Emory Vaccine Centre, Emory National Primate Research Centre, Emory University, Atlanta, Georgia, USA
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