Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice

Abstract

Background Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = − 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = − 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 μmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. Conclusions PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

Liver injury and prolonged hospitalization as indicators of severity in patients with adenovirus infections

“…Additionaly, CD4 + T cells enhanced production of IFN-γ by NK cells [ 27 ] and NK cells positively regulated CD8 + T cells via secreting IFN-γ [ 28 ]. What’s more, increased IFN-γ expression in CD4 + T and CD8 + T cells was related with decreased bilirubin production and exacerbated liver immunopathology [ 29 – 30 ], which might explained the cause of the positive relationship of AST/ALT with IFN-γ level partly.…”

The Neonatal Innate Immune Response to Sepsis: Checkpoint Proteins as Novel Mediators of This Response and as Possible Therapeutic/Diagnostic Levers

“…PD-1 expression has also been studied in the context of inflammation due to biliary atresia. Infants diagnosed with biliary atresia have been found to have increased PD-1 expression on hepatic and circulating T-cells, as well as lower levels of IFN-γ in the liver ( 121 ). In a virus-induced biliary atresia model in mice, PD-1 blockade has been shown to lead to increased levels of AST, ALT, and IFN-γ, suggesting that PD-1 plays a role in mitigating liver injury in this disease process.…”