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

Abstract

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 p110δ isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110δ gene (p110δ) succumbed acutely to nonlethal dose LPS challenge. The susceptibility of p110δ 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 p110δ Tregs abrogated exaggerated neutrophil activity, increased neutrophil apoptosis, and rescued p110δ 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 δ 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.

The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells

“…For example, we previously showed that depletion of Tregs leads to exaggerated CD4 + T cell response in bacteria and LPS-induced acute inflammation models (61). In another study, we demonstrated that reduced Treg numbers also leads to enhanced neutrophil activity in LPS-induced inflammation (150). Hence, it follows that reduced Treg numbers simultaneously affects CD4 + T cells and neutrophils.…”

“…Richards et al showed that Tregs limit inflammation in the skin by inhibiting neutrophil accumulation and survival (149). We recently showed that reduced Treg numbers in mice leads to exaggerated neutrophil activity resulting in mortality in endotoxic shock (150). We also found that Tregs regulate survival and activity of human and murine neutrophils and co-culture of Tregs and neutrophils increases neutrophil apoptosis (150).…”

“…We recently showed that reduced Treg numbers in mice leads to exaggerated neutrophil activity resulting in mortality in endotoxic shock (150). We also found that Tregs regulate survival and activity of human and murine neutrophils and co-culture of Tregs and neutrophils increases neutrophil apoptosis (150). This is in line with the work of Lewkowicz et al which showed that LPS-activated Tregs inhibit neutrophil function and promote their apoptosis (151).…”

Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets

“…Defective Treg function were demonstrated in all these diseases, and Treg therapy ameliorated them [ 67 ]. Reduced Treg numbers in mice leads to exaggerated neutrophil activity resulting in mortality in endotoxic shock [ 68 ]. Tregs regulate survival and activity of human and murine neutrophils, and co-cultures of Tregs and neutrophils increases neutrophil apoptosis [ 68 ].…”

Phospholipid signaling in innate immune cells

“…The importance of the PI3K pathway in human immune disorders is further emphasized by the presence of activating mutations in p110δ in a number of primary immune deficiency patients, who suffer particularly from recurring respiratory tract infections (105). In contrast, deficiency in PI3Kδ signaling decreases Treg number and increases neutrophil numbers, which can cause an increase in endotoxic shock-related mortality (106).…”