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The immune landscape of the “deregulated host response” in sepsis: newly emerging MDSCs with high expression of CD47 leads to B cell suppression via App-CD74 signaling [RNA-seq]

ABSTRACT: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, how this dysregulation occurs remains unclear. Herein, we used scRNA-seq to define the immune landscape of infection and found that when sepsis occurred, adaptive immunity was acutely and strongly suppressed, which manifested as a striking increase in the number of myeloidderived suppressor cells (MDSCs), a decrease in the number of lymphocytes and drastic downregulation of the expression levels of B-cell-related genes and MHC class II molecules. Transcriptomic analysis showed that systemic immunosuppression occurred not only in the peripheral blood but also in all other immune compartments, including the spleen, lymph nodes, and bone marrow. Patients diagnosed with infection in the emergency department with extremely low expression levels of adaptive immunity related genes had a high risk for developing sepsis. CD47 was identified as the key molecule that triggered this immunosuppression by inducing the production of amyloid-b precursor protein (App), which caused adaptive immunosuppression via B-cell suppression. Our study outlines a framework for how the dysregulated host response occurs and provides translational opportunities for sepsis immunotherapies

ORGANISM(S): Mus musculus

PROVIDER: GSE222996 | GEO | 2025/03/12

REPOSITORIES: GEO

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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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The immune landscape of the “deregulated host response” in sepsis: newly emerging MDSCs with high expression of CD47 leads to B cell suppression via App-CD74 signaling [RNA-seq]

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