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[Display omitted] • Immune inflammation and immunosuppression coexist on the spleen during the course of sepsis. • Splenectomy could protect sepsis mice from exhaustion of immune cell by reduction of the expression of Treg cells and PD-1/PD-L1 axis in immune cell during the immunosuppressive stage of sepsis. • Splenectomy also could reduce liver and lung injury possibly by TIM 3 and/or Galectin-9 axis. • The spleen is an important regulator of the occurrence and development of sepsis. The role of the spleen in sepsis is still controversial. Therefore, we investigated the effect of the spleen on sepsis-induced immune dysfunction in C57BL/6 mice subjected to caecal ligation and puncture (CLP). Changes in different immune cells and apoptotic cells in the spleen and peripheral blood were observed 4, 24 and 48 h after CLP. Then, we determined that 48 h following CLP was the most significant period of immunosuppression. Next, we divided the mice into four groups: control, CLP, CLP + spx (splenectomy 48 h after CLP) and spx + CLP (splenectomy surgery two weeks before CLP). Compared with the CLP mice, the CLP + spx and spx + CLP mice had improved survival rates and organ injuries, increased expression of inflammatory factors, a decreased proportion of regulatory T cells (Tregs), and reduced expression of the genes involved in the programmed cell death 1 and its ligand 1 (PD1-PDL1) pathway in immune cells and T-cell immunoglobulin-mucin domain 3 (Tim 3) and Galectin9 in the liver and lungs after 72 h in late-phase sepsis. In addition, the expression of PD-1 was significantly reduced in T cells in spx + CLP mice, and the expression of PD-L1 in myeloid-derived suppressor cells (MDSCs) was reduced in the CLP + spx group, especially in macrophages. These findings suggested that splenectomy could protect septic mice from exhaustion of immune cells by reducing the proliferation of Treg cells and expression of the PD-1/PD-L1 axis in immune cells during the immunosuppressive stage of sepsis. Splenectomy could also reduce liver and lung injuries possibly via the Tim 3 and/or Galectin-9 axis. The spleen is an important regulator of the occurrence and development of sepsis, which provides a new perspective to improve the prognosis of sepsis by regulating the spleen. [ABSTRACT FROM AUTHOR]