PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction.
BACKGROUND
Lymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown.


METHODS
Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined.


RESULTS
Expression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were up-regulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance.


CONCLUSIONS
PD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.
Clinical Research Center, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, PR China.
Yan
Y
Zhang
Ying
Y
Zhou
Jingsheng
J
Lou
Jinbao
J
Li
Lulong
L
Bo
Keming
K
Zhu
Xiaojian
X
Wan
Xiaoming
X
Deng
Zailong
Z
Cai
D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D008214:Lymphocytes / Q000166:cytology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology*; D011897:Random Allocation; D018805:Sepsis / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate
D000906:Antibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse