The predictive role of early activation of natural killer cells in septic shock

Recently, several studies about the role of natural killer (NK) cells in sepsis have been highlighted. In an earlier study, we characterized the abnormalities of circulating lymphocytes in 52 patients with septic shock during the first 28 days in the intensive care unit. Our results confirm and expand some previous reports. We found that patients who did not survive exhibited less NK cell (CD3−CD56+) depletion than survivors and that these NK cells expressed CD69+ and CD57+. These data demonstrate that NK cells are key participants in septic shock because patients who survived have more depletion and expressed less early activation and differentiation.

counts and relative concentrations of natural killer (NK) cells were signifi cantly higher in patients who died.
In an earlier study, also published in Critical Care, we characterized the abnormalities of lymphocytes in 52 patients with septic shock during the fi rst 28 days in the ICU [2]. Th irty-six healthy subjects served as controls. Th e study design was approved by the university hospital ethics committee, and all participants or their next of kin provided written informed consent. Table 1 shows the signifi cant diff erences found in the counts and percentages of lymphocyte subpopulations during the fi rst week of follow-up. Like previous investi gators, we have found a reduced count of circulating NK cells in patients with septic shock, independently of their outcome [1,3]. Although patients who did not survive exhibited less NK cell depletion than survivors at ICU admission, there were no diff erences in CD56 + CD3cell counts in blood between survivors and non-survivors. Th ese data are slightly in agreement with those reported by Andaluz-Ojeda and colleagues [1], who found that patients with the highest NK cell number had the lowest probability to survive. However, unlike Giamarellos-Bourboulis and colleagues [4], we did not fi nd higher percentages of NK cells in patients who did not survive.
Using CD69 and CD57 surface antigens, we determined the counts and distributions of the activation stage of NK cells (CD3 − CD56 + ) by fl ow cytometry. We obtained a signifi cant increase in the counts and percentages of the CD3 − CD56 + CD69 + cells in non-survivors at ICU admission and on day 3 ( Figure 1). Th e mean fl uorescence intensity for CD56 + CD3 − CD69 + cells was also significantly higher in non-survival patients than in survivors or controls (30.6 ± 4.2 versus 20.3 ± 2.6 and 18.3 ± 0.9, respectively; P <0.05 for both). CD69 is rapidly induced in NK cells after activation and its role in NK cytotoxicity has been demonstrated in humans [5].
We further found a signifi cantly higher percentage of CD3 − CD56 + CD57 + NK cells in non-survival patients than in survivors and controls at ICU admission (70.8% ± 3.3% versus 57.3% ± 9.2% and 53.6% ± 3.7%, respectively; P <0.05). Non-survivors had a strong but not signifi cant trend toward an increase of CD3 − CD56 + CD57 + NK cell count (94.8 ± 7.3 versus 56.9 ± 12.4 cells per cubic millimeter). Th e expression of CD57, a long-lived marker and highly diff erentiated eff ector of NK cells, is increased in septic shock patients who died.
Th ese data demonstrate an important role of NK cells as key participants in the early infl ammatory response during septic shock. Patients who did not survive exhibited less NK cell depletion than survivors and these cells were very early activated and rapidly diff er entiated. We propose to asses NK cell phenotype and func tions for

Abstract
Recently, several studies about the role of natural killer (NK) cells in sepsis have been highlighted. In an earlier study, we characterized the abnormalities of circulating lymphocytes in 52 patients with septic shock during the fi rst 28 days in the intensive care unit. Our results confi rm and expand some previous reports. We found that patients who did not survive exhibited less NK cell (CD3 − CD56 + ) depletion than survivors and that these NK cells expressed CD69 + and CD57 + . These data demonstrate that NK cells are key participants in septic shock because patients who survived have more depletion and expressed less early activation and diff erentiation.  Values are expressed as the mean percentage ± standard deviation (A) or as the mean of cells per microliter ± standard deviation (B). Data from non-survival patients, survivors, and healthy control subjects are shown in red, green, and blue, respectively. The Mann-Whitney U test for non-parametric data was used to analyze diff erences between the groups, and analysis of variance followed by Wilcoxon signed-rank tests were used for within-group analyses. *P <0.05 for survivors or non-survivors versus controls; † P <0.05 for survivors versus non-survivors; ‡ P <0.05 for each follow-up time versus intensive care unit admission.