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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 p110d isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110d gene (p110δD910A) succumbed acutely to nonlethal dose LPS challenge. The susceptibility of p110δD910A 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 p110δD910A Tregs abrogated exaggerated neutrophil activity, increased neutrophil apoptosis, and rescued p110δD910A 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 d 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. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance, and defects in Treg function have been linked to several autoimmune diseases. We previously reported that depletion of Tregs resulted in mortality to an otherwise nonlethal dose of LPS or Escherichia coli challenge. In this study, we investigated the mechanism by which Treg depletion leads to enhanced susceptibility to LPS. Using different murine lymphocyte gene knockout models, we show that the enhanced sensitivity to LPS following Treg depletion is mediated by T cells. SCID or RAG1-deficient mice, which lack T and B cells, do not show enhanced susceptibility to LPS. However, reconstitution of SCID mice with wild-type CD4+ T cells restored Treg depletion-induced sensitivity to LPS. This CD4+ T cell-mediated hypersensitivity to LPS challenge in the absence of Tregs was also observed upon reconstitution of SCID mice with CD4+ T cells from CD25 knockout mice (which lack functional Tregs). Additionally, depletion of Tregs leads to increased CD4+ T cell proliferation and proinflammatory cytokine production in response to LPS challenge. Some CD4+ T cells express TLR4, and pretreatment of CD4+ T cells with LPS dramatically enhanced their ability to induce inflammatory cytokine production by macrophages. Collectively, our results indicate that in the absence of functional Tregs, CD4+ T cells are pathologic and contribute to exaggerated immune activation that is detrimental for survival in LPS-induced acute inflammation. Our data also provide evidence for direct activation of CD4+ T cells by LPS through TLR4. [ABSTRACT FROM AUTHOR]