Deficiency of Phosphatidylinositol 3-Kinase delta Signaling Leads to Diminished Numbers of Regulatory T Cells and Increased Neutrophil Activity Resulting in Mortality Due to Endotoxic Shock

摘要

Despite decades of clinical and biomedical research, the pathogenesis of sepsis and its spectrum of diseases (severe sepsis and septic shock), which are leading causes of death in intensive care units, are still poorly understood. In this article, we show that signaling via the p110 delta isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110 delta gene (p110 delta(D910A)) succumbed acutely to nonlethal dose LPS challenge. The susceptibility of p110 delta(D910A) mice to LPS was associated with increased neutrophil numbers and activities in the tissues, due in part to delayed apoptosis resulting mostly from inherent reduced regulatory T cell (Treg) numbers. Adoptive transfer of wild-type or p110 delta(D910A) Tregs abrogated exaggerated neutrophil activity, increased neutrophil apoptosis, and rescued p110 delta(D910A) mice from mortality after LPS challenge. We confirmed the clinical relevance of these findings by showing that human Tregs also regulate neutrophil function and survival. Collectively, our results show that PI3K delta is essential for survival during sepsis. In addition, our data highlight the importance of Tregs in regulating the pathogenesis of sepsis and septic shock via their effects on neutrophil survival and function, and provide evidence of regulation of innate immunity by cells of the adaptive immune system.