Toll-like receptors expression and interferon-γ production by NK cells in human sepsis

Fernando Souza-Fonseca-Guimaraes,Jean-Marc Cavaillon,Minou Adib-Conquy,François Philippart,Benoît Misset,Marianna Parlato

doi:10.1186/cc11838

Fernando Souza-Fonseca-Guimaraes, Jean-Marc Cavaillon + Show 4 more

Open Access

https://doi.org/10.1186/cc11838

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Abstract

IntroductionDuring the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, particularly interferon-gamma (IFN-γ). In addition to their beneficial effects against infection, NK cells may play a detrimental role during systemic inflammation, causing lethality during sepsis. Little is known on the immune status of NK cells in patients with systemic inflammatory response syndrome (SIRS) or sepsis in terms of cell surface markers expression and IFN-γ production.MethodsWe investigated 27 sepsis patients and 11 patients with non-infectious SIRS. CD56bright and CD56dim NK cell subsets were identified by flow cytometry and Toll-like receptor (TLR)2, TLR4, TLR9, CX3CR1, CD16 and CD69 expression were analyzed, as well as ex vivo IFN-γ production by NK cells in whole blood samples.ResultsWe first showed that in NK cells from healthy controls, TLR2 and TLR4 expression is mainly intracellular, similarly to TLR9. Intracellular levels of TLR2 and TLR4, in both CD56bright and CD56dim NK cell subsets from sepsis patients, were increased compared to healthy subjects. In addition, the percentage of CD69+ cells was higher among NK cells of sepsis patients. No difference was observed for TLR9, CX3CR1, and CD16 expression. The ex vivo stimulation by TLR4 or TLR9 agonists, or whole bacteria in synergy with accessory cytokines (IL-15+IL-18), resulted in significant production of IFN-γ by NK cells of healthy controls. In contrast, for SIRS and sepsis patients this response was dramatically reduced.ConclusionsThis study reports for the first time an intracellular expression of TLR2 and TLR4 in human NK cells. Surface TLR4 expression allows discriminating sepsis and SIRS. Furthermore, during these pathologies, NK cells undergo an alteration of their immune status characterized by a profound reduction of their capacity to release IFN-γ.

Highlights

During the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, interferon-gamma (IFN-g)
This study reports for the first time an intracellular expression of TLR2 and TLR4 in human NK cells
We demonstrated a defect of NK cells for both CD69 upregulation and IFN-g production ex vivo in response to accessory cytokines and pathogen-associated molecular pattern (PAMP), or accessory cytokines and whole bacteria in sepsis and systemic inflammatory response syndrome (SIRS) patients

Summary

Introduction

During the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, interferon-gamma (IFN-g). Little is known on the immune status of NK cells in patients with systemic inflammatory response syndrome (SIRS) or sepsis in terms of cell surface markers expression and IFN-g production. CD56bright and CD56dim NK cell subsets were identified by flow cytometry and Toll-like receptor (TLR), TLR4, TLR9, CX3CR1, CD16 and CD69 expression were analyzed, as well as ex vivo IFN-g production by NK cells in whole blood samples Both severe sepsis and systemic inflammatory response syndrome (SIRS) are characterized by an exacerbated inflammatory response and a cytokine storm [1]. Sepsis and SIRS patients undergo a compensatory anti-inflammatory response syndrome (CARS) [2] This modification of immune status, called reprogramming, has been regularly reported for circulating monocytes, neutrophils and lymphocytes in sepsis [3,4,5]. Deleterious roles of NK cells have been reported in animal models after polymicrobial intra-abdominal sepsis, Escherichia coli intraperitoneal injection, Streptococcus pyogenes intravenous injection, cytokine-induced SIRS, and in a polytrauma model

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