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

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 myeloid-derived 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-β 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.