title: Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients.
abstract: BACKGROUND
  Studies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression.
  
  
  METHODS
  Nineteen septic shock patients and 22 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis in lymphocyte subpopulations and PD-1/PD-L1 expression on peripheral T cells, B cells and monocytes were measured using flow cytometry. Apoptosis of T cells induced by TNFα or T-cell receptor ligation in vitro and effects of anti-PD-L1 antibody administration were measured by flow cytometry. CD14+ monocytes of septic shock patients were purified and incubated with either lipopolysaccharide, anti-PD-L1 antibody, isotype antibody, or a combination of lipopolysaccharide and anti-PD-L1 antibody or isotype antibody. Supernatants were harvested to examine production of cytokines by ELISA.
  
  
  RESULTS
  Compared with healthy controls, septic shock induced a marked increase in apoptosis as detected by the annexin-V binding and active caspase-3 on CD4+ T cells, CD8+ T cells and CD19+ B cells. Expression of PD-1 on T cells and of PD-L1 on monocytes was dramatically upregulated in septic shock patients. PD-1/PD-L1 pathway blockade in vitro with anti-PD-L1 antibody decreased apoptosis of T cells induced by TNFα or T-cell receptor ligation. Meanwhile, this blockade potentiated the lipopolysaccharide-induced TNFα and IL-6 production and decreased IL-10 production by monocytes in vitro.
  
  
  CONCLUSIONS
  The expression of PD-1 on T cells and PD-L1 on monocytes was upregulated in septic shock patients. The PD-1/PD-L1 pathway might play an essential role in sepsis-induced immunosuppression.
authors.affiliation: Clinical Research Center, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, PR China. czl8003@163.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jinbao
authors.initials: J
authors.lastname: Li
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Lou
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lulong
authors.initials: L
authors.lastname: Bo
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhu
authors.forename: Keming
authors.initials: K
authors.lastname: Zhu
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wan
authors.forename: Zailong
authors.initials: Z
authors.lastname: Cai
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Deng
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011446:Prospective Studies; D012772:Shock, Septic / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor