Major trauma-induced tissue injury causes a dysregulation of the immune system. Severe systemic inflammation occurs early after the insult. Later on, an enhanced risk for life-threatening opportunistic infections develops that culminates at the end of the first week after trauma. CD56 bright Natural killer (NK) cells play a key role in the defense against infection due to their rapid release of Interferon (IFN) γ in response to Interleukin (IL) 12. NK cells are impaired in IFN-γ synthesis after severe injury due to a disturbed IL-12/IFN-γ axis. Thereby, a circulating factor mediates extrinsic suppression of NK cells. Yet unknown cell-intrinsic mechanisms manifest by day 8 after trauma and render NK cells unresponsive to stimulatory cytokines. In the present study, we investigated the origin of such late NK cell-intrinsic suppression after major trauma. Peripheral blood mononuclear cells (PBMC) were isolated from patients 8 day after severe injury and from healthy control subjects and were stimulated with inactivated Staphylococcus aureus . The expression of diverse cytokine receptors, intracellular signaling molecules, and the secretion of IFN-γ by CD56 bright NK cells were examined. After stimulation with S. aureus , NK cells from patients expressed enhanced levels of c-kit/CD117 that inversely correlated with IFN-γ synthesis and IL-12 receptor (IL-12R) β2 expression. Supplementation with IL-15 and inhibition of the transforming growth factor receptor (TGF-βR) I reduced CD117 expression and increased the level of IL-12Rβ2 and IFN-γ. NK cells from patients showed reduced phosphorylation of mammalian target of rapamycin (mTOR). Addition of IL-15 at least partly restored mTOR phosphorylation and increased IL-12Rβ2 expression. The reduced mTOR phosphorylation after severe injury was cell-intrinsic as it was not induced by serum factors. Inhibition of mTOR in purified NK cells from healthy donors by rapamycin decreased the synthesis of IFN-γ. Thus, impaired mTOR phosphorylation in response to a microbial challenge contributes to the cell-intrinsic mechanisms that underlie NK cell dysregulation after trauma. Restoration of the mTOR phosphorylation capacity along with inhibition of the TGF-βRI signaling in NK cells after severe injury might improve the immune defense against opportunistic infections.

Major traumatic and surgical injury increase the risk for infectious complications due to immune dysregulation. Upon stimulation with interleukin (IL) 12 by monocyte/macrophages, natural killer (NK) cells release interferon (IFN) γ that supports the elimination of the pathogen. In the present study, we investigated the impact of invasive spine surgery on the relationship between monocytes and NK cells upon exposure to Staphylococcus aureus. Mononuclear cells and serum were isolated from peripheral blood of patients before and up to 8 d after surgery and stimulated with inactivated S. aureus bacteria. NK cell and monocyte function were determined by flow cytometry. NK cells continuously lost their ability to produce IFN-γ during the first week after surgery independently from monocyte-derived IL-12 secretion. IFN-γ synthesis was minimal on day 8 and was associated with decreased expression of the IL-12 receptor and activation of transcription factors required for IFNG gene transcription. Addition of recombinant IL-12 could at least partially restore NK cell function. Pre-operative levels of growth/differentiation factor (GDF) 15 in the serum correlated with the extent of NK cell suppression and with hospitalization. Thus, NK cell suppression after major surgery might represent a therapeutic target to improve the immune defense against opportunistic infections.