DOCK2 protects against bacterial sepsis by constraining T helper 1 response
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ABSTRACT:
PROVIDER: PRJNA1266715 | ENA |
REPOSITORIES: ENA
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Project description:Sepsis is a systemic host response to infection with life-threatening consequence, which ranks among the top 10 causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary. Here, we identified dedicator of cytokinesis 2 (DOCK2) is a critical downregulating factor for lipopolysaccharide (LPS) signal pathways. DOCK2-deficient mice were highly sensitive to LPS-induced sepsis and Escherichia coli sepsis with increased levels of inflammatory cytokines, especially interferon-g (IFN-g), which were mainly due to hyperresponsive T helper 1 (Th1) cells. Ulteriorly, we verified the vital role of DOCK2-mediated Th1 cells in sepsis by neutralizing both IFN-g and CD4 and found both of which blockade reduced the severity of sepsis in Dock2-/- mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate. Taken together, our data indicate that DOCK2 acts as a protective role in regulating systemic inflammation and multi-organ injury in bacterial sepsis by constraining Th1 response.
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Project description:Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases.
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Project description:Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases.
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Project description:Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases.
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Project description:Our experiments examined T-lymphocyte numbers and effector-functions in peritoneal contamination and infection (PCI) a mouse model of sepsis. One of our main questions was how T-lymphocytes reconstitute after sepsis-induced lymphopenia. We investigated the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Sepsis is an immunological dysfunction against pathogens leading to inflammation with massive cytokine production. Simultaneously immunosuppression occurs e.g. lymphopenia, which is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. More than 50% of T-cells undergo apoptosis shortly after sepsis-induction. However, 8 days after sepsis onset, surviving mice present normal lymphocyte counts. Theoretically, T-cells could reconstitute in two different ways. Firstly, the diminished pool of T-cells is replenished by newly in thymus produced T-cells with new diverse T-cell-receptors (TCRs). Alternatively, remaining T-cells start to proliferate until reaching normal cell count. If this was the case all divided cells shared the same TCRs as primary cells. This could lead to a narrowed TCR diversity within a quantitative normalized T-cell pool and would be an explanation for the long-lasting immune incompetence. To address the question how T-cells recover from lymphopenia we applied next generation sequencing (NGS) to analyse TCR diversity in septic and healthy mice. One group of septic mice received Interleukin-7 (IL-7), an interleukin which regulates T-cell homeostasis and is a promising therapeutically approach for septic patients. 50000 sequences per mouse were analyzed and the three different groups (controls, sepsis, sepsis + IL-7 treatment) compared regarding their diversity. The sequenced raw data (fastq) are uploaded in this library.
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