title: High circulating CD39(+) regulatory T cells predict poor survival for sepsis patients.
abstract: BACKGROUND
  Sepsis encompasses two phases, the 'hyper'-reactive phase and the 'hypo'-reactive phase. The initial inflammatory stage is quickly counterbalanced by an anti-inflammatory response, which compromises the immune system, leading to immune suppression. Regulatory T cells (Tregs) have been implicated in the pathogenesis of sepsis by inducing immunosuppression; however, the role of CD39(+) Tregs in the process of sepsis is uncertain. This study investigated the dynamic levels of CD39(+) Tregs and their phenotypic change in sepsis.
  
  
  METHODS
  Fourteen patients with systemic inflammatory response syndrome (SIRS), 42 patients with sepsis, and 14 healthy controls were enrolled. Sequential blood samples were used to analyze the numbers of CD39(+) Tregs and their phenotypic changes. Survival at 28 days was used to evaluate the capacity of CD39(+) Treg levels to predict mortality in sepsis patients.
  
  
  RESULTS
  Sepsis patients displayed a high percentage (3.13%, 1.46%, and 0.35%, respectively) and mean fluorescence intensity (MFI) (59.65, 29.7, and 24.3, respectively) of CD39(+) Tregs compared with SIRS patients and healthy subjects. High-level expression of CD39(+) Tregs was correlated with the severity of sepsis, which was reflected by the sepsis-related organ failure assessment score (r=0.322 and r=0.31, respectively). In addition, the expression of CD39(+) Tregs was associated with survival of sepsis patients (p<0.01). By receiver-operating characteristic (ROC) curve analysis, the percentage and MFI of CD39(+) Tregs showed similar sensitivities and specificities to predict mortality (74.2% and 85.1%, and 73.9% and 84.1%, respectively). Using Kaplan-Meier curves to assess the impact of CD39(+) Tregs percentage and MFI on overall survival, we found that a high CD39(+) Tregs percentage (p<0.001; >4.1%) and MFI (p<0.001; >49.2) were significantly associated with mortality. Phenotypically, CD39(+) Tregs from sepsis patients showed high expression of CD38 and PD-1 (p<0.01 and p<0.01 respectively).
  
  
  CONCLUSIONS
  Increased expression of CD39(+) Tregs was associated with a poor prognosis for sepsis patients, which suggests that CD39(+) Treg levels could be used as a biomarker to predict the outcome of sepsis patients.
authors.affiliation: Medical School of Chinese PLA, Beijing, China; The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Huihuang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Ruonan
authors.initials: R
authors.lastname: Xu
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.affiliation: The Institute of Clinical Examination Center, Beijing 302 Hospital, Beijing, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Bao
authors.affiliation: Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Ji
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Mu
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Sun
authors.affiliation: The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Xu
authors.affiliation: Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China. Electronic address: zhangzheng1975@aliyun.com.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Medical School of Chinese PLA, Beijing, China; Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China. Electronic address: fswang302@163.com.
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis*; D001081:Apyrase / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000276:immunology / Q000401:mortality*; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology / Q000401:mortality; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D001081:Apyrase; C067869:CD39 antigen
keywords: CD39; Prognosis; Regulatory T cell; Sepsis