Re lymphopenia, we did not assess functions of other cells (ie, monocytes, dendritic cells or Treg) that might have significant buy CASIN influence on NK cells functions. Finally, NK cells are present in the lungs at homeostasis, where their frequency is greater than in liver, peripheral blood mononuclear cells, spleen, or lymph nodes [9]. NK cells can be rapidly recruited to the sites of inflammation and we must keep in mind that, with regards to the concept of 18325633 compartmentalization, that the status of NK cells within tissues may differ [10]. Overall, the present study provides the first report of extensive monitoring of the phenotype and functions of NK cells in critically-ill septic patients. Importantly, our results contrast with what has been reported in murine models [11?7]. Indeed, most murine models of septic shock have demonstrated a deleterious role of NK cells, with a protective effect on survival of NK-cell depletion. However, there are obvious differences between murine Lixisenatide site Sepsis model and human data generated at bedside that could prevent direct comparison and/or explain apparent discrepancies. Conversely to patients that exhibit significant heterogeneity, miceare genetically identical, have same age and gender, are challenged in the same way (pathogen type, dose and route of administration) and present no confounding factors such as other treatments or comorbidities. Also, one of the major differences between the murine sepsis model and the human data provided here is the delay between the onset 1662274 of sepsis and biological investigations. In the animal model, the timing is very short and controlled, whereas in patients, only the time from admission is known precisely whereas the time from sepsis onset can vary considerably. However, the timing of sampling in our study corresponded to “real-life” situations with regards to the development of future immuno-interventions. Transposed to human septic shock, the murine experiments might have prompted us to design an immuno-therapeutic trial with early NK depletion. Instead, the results of this work show that, in critically-ill septic patients, NK cells rapidly exhibit a normal or hypo-responsiveness status that may be part of the “immunoparalysis” (or tolerance), as reported for monocytes [6?]. This hyporesponsiveness particularly involves patients with septic shock and IFN-c secretion and is in complete agreement with the recent report of NK cell tolerance in term of inflammatory cytokines production (including IFN-c) in a murine model of experimental bacterial sepsis [46]. These preliminary results and, aside from the supposed detrimental role of NK cells on the early amplification in the inflammatory response, the fact that NK cells also have beneficial anti-infectious (especially against CMV) as well as antiinflammatory properties [47], actually 
support that therapeutic immuno-intervention in critically-ill septic patients could be directed towards stimulation of NK-cell functions [48].Supporting InformationTable SStudies of NK cells in humans with Sepsis orSIRS. (DOCX)Table S2 Numbers of lymphocyte subpopulations at admission to the ICU in healthy, SIRS and Sepsis groups. (DOCX) Table S3 Serum cytokine levels in ICU patients with SIRS and Sepsis. (DOCX) Methods S1 Additional informations on immunological and 
statistical methodologies. (DOCX)AcknowledgmentsThe authors thank the patients who enrolled in this study, and the physicians, nurses, and secretaries at the Department of Reanimat.Re lymphopenia, we did not assess functions of other cells (ie, monocytes, dendritic cells or Treg) that might have significant influence on NK cells functions. Finally, NK cells are present in the lungs at homeostasis, where their frequency is greater than in liver, peripheral blood mononuclear cells, spleen, or lymph nodes [9]. NK cells can be rapidly recruited to the sites of inflammation and we must keep in mind that, with regards to the concept of 18325633 compartmentalization, that the status of NK cells within tissues may differ [10]. Overall, the present study provides the first report of extensive monitoring of the phenotype and functions of NK cells in critically-ill septic patients. Importantly, our results contrast with what has been reported in murine models [11?7]. Indeed, most murine models of septic shock have demonstrated a deleterious role of NK cells, with a protective effect on survival of NK-cell depletion. However, there are obvious differences between murine sepsis model and human data generated at bedside that could prevent direct comparison and/or explain apparent discrepancies. Conversely to patients that exhibit significant heterogeneity, miceare genetically identical, have same age and gender, are challenged in the same way (pathogen type, dose and route of administration) and present no confounding factors such as other treatments or comorbidities. Also, one of the major differences between the murine sepsis model and the human data provided here is the delay between the onset 1662274 of sepsis and biological investigations. In the animal model, the timing is very short and controlled, whereas in patients, only the time from admission is known precisely whereas the time from sepsis onset can vary considerably. However, the timing of sampling in our study corresponded to “real-life” situations with regards to the development of future immuno-interventions. Transposed to human septic shock, the murine experiments might have prompted us to design an immuno-therapeutic trial with early NK depletion. Instead, the results of this work show that, in critically-ill septic patients, NK cells rapidly exhibit a normal or hypo-responsiveness status that may be part of the “immunoparalysis” (or tolerance), as reported for monocytes [6?]. This hyporesponsiveness particularly involves patients with septic shock and IFN-c secretion and is in complete agreement with the recent report of NK cell tolerance in term of inflammatory cytokines production (including IFN-c) in a murine model of experimental bacterial sepsis [46]. These preliminary results and, aside from the supposed detrimental role of NK cells on the early amplification in the inflammatory response, the fact that NK cells also have beneficial anti-infectious (especially against CMV) as well as antiinflammatory properties [47], actually support that therapeutic immuno-intervention in critically-ill septic patients could be directed towards stimulation of NK-cell functions [48].Supporting InformationTable SStudies of NK cells in humans with Sepsis orSIRS. (DOCX)Table S2 Numbers of lymphocyte subpopulations at admission to the ICU in healthy, SIRS and Sepsis groups. (DOCX) Table S3 Serum cytokine levels in ICU patients with SIRS and Sepsis. (DOCX) Methods S1 Additional informations on immunological and statistical methodologies. (DOCX)AcknowledgmentsThe authors thank the patients who enrolled in this study, and the physicians, nurses, and secretaries at the Department of Reanimat.