Sepsis is defined as multi-organ dysfunction caused by dysregulated host response to infection. This dysregulated host response includes enhanced inflammatory responses and suppressed adaptive immunity, but the molecular mechanisms behind it have not yet been elucidated. CD72, a type II transmembrane protein that is primarily expressed in B cells, was found to play an immunomodulatory role in the immune system and was associated with mortality in patients with sepsis. However, whether CD72 affects the pathogenesis of sepsis by influencing the immune response remains unclear.We first collected peripheral blood from 40 healthy volunteers and 57 septic patients and analyzed the mRNA levels of CD72 and the expression of its soluble form sCD72 using Realtime-PCR and ELISA. We then employed the CRISPR/Cas9 system to generate CD72 knockout mice (CD72-KO) and established a cecal ligation and puncture (CLP) model to analyze the effects of CD72 gene deletion on the survival, organ injury and immune response of septic mice by Kaplan-Meier survival analysis, pathological sections and flow cytometry. We also observe the effects of excess sCD72 on survival and immune response in sepsis by injecting recombinant CD72 protein into mice. Finally, the mechanism of sCD72 affecting sepsis immunity was analyzed by fluorescence staining, confocal microscopy and flow cytometry.We found that when sepsis occurs, the levels of CD72 mRNA and cell surface CD72 in immune cells decrease, while the level of soluble sCD72 in the blood increases significantly. Excessive sCD72 increased sepsis mortality in a dose-dependent manner, which can bind to CD100 on the surface of T cells and enter the cytoplasm, leading to impaired T cell functions, including a decrease in CD4+IFN-γ+, CD8+Perforin+, CD8+GZMB+, and CD8+FASL+ population and an increase in inflammatory CD4+TNF-α+ population, thereby suppressing adaptive immunity while enhancing inflammatory response.The immunosuppression of sepsis has been recognized, but the underlying mechanism has not been fully elucidated. Our study identified for the first time that sCD72 is an important mediator that cause adaptive immunosuppression during sepsis, which leads to T cell suppression by competitively binding to CD100 on the surface of T cells. Our study provides novel insights in our understanding of sepsis-related immunosuppression and may provide translational opportunities for the design of new diagnostic biomarkers and therapeutic targets for sepsis.Copyright © 2024 Elsevier B.V. All rights reserved.