摘要
Background and Aims:Programmed cell death-1(PD-1)plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood.This study aimed to explore the role of PD-1 in CD8^(+)T lymphocyte dysfunction in hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).Methods:Thirty patients with HBV-ACLF and 30 healthy controls(HCs)were recruited.The differences in the numbers and functions of CD8^(+)T lymphocytes,PD-1 and glucose transporter-1(Glut1)expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed.In vitro,the CD8^(+)T lymphocytes from HCs were cultured(HC group)and the CD8^(+)T lymphocytes from ACLF patients were cultured with PD-L1-IgG(ACLF+PD-1 group)or IgG(ACLF group).The numbers and functions of CD8^(+)T lymphocytes,PD-1 expression,glycogen uptake capacity,and Glut1,hexokinase-2(HK2),and pyruvate kinase(PKM2)expression were analyzed among the HC group,ACLF group and ACLF+PD-1group.Results:The absolute numbers of CD8^(+)T lymphocytes in the peripheral blood from patients with HBVACLF were lower than in the HCs(p<0.001).The expression of PD-1 in peripheral blood CD8^(+)T lymphocytes was lower in HCs than in patients with HBV-ACLF(p=0.021).Compared with HCs,PD-1 expression was increased(p=0.021)and Glut1 expression was decreased(p=0.016)in CD8^(+)T lymphocytes from the HBV-ACLF group.In vitro,glycogen uptake and functions of ACLF CD8^(+)T lymphocytes were significantly lower than that in HCs(p=0.017;all p<0.001).When PD-1/PD-L1 was activated,the glycogen uptake rate and expression levels of Glut1,HK2,and PKM2 showed a decreasing trend(ACLF+PD-1 group compared to ACLF group,all p<0.05).The functions of CD8^(+)T lymphocytes in the ACLF+PD-1 group[using biomarkers of Ki67,CD69,IL-2,interferon-gamma,and tumor necrosis factor-alpha-were lower than in the ACLF group(all p<0.05).Conclusions:CD8^(+)T lymphocyte dysfunction is observed in patients with HBV-ACLF.PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.
基金
This study was funded by the National Natural Science Foundation of China(81700562)
the Shanxi Outstanding Youth Fund Project(201801D211009)
the Shanxi Province Key Program Project(201903D321125)
the Shanxi Province 136 Revitalization Medical Project(General Surgery Department)
International Cooperation in Key R&D Projects of Shanxi Province(No.201903D421026).
