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 \xa0=\u2009−\u20090.25, p \xa0=\u20090.05; PD-1 + CD8 + T cells in liver vs. IFN-γ concentration, r \xa0=\u2009−\u20090.39, p \xa0=\u20090.004). 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\u2009±\u20093.43% vs. 21.26\u2009±\u20095.32% IFN-γ + in hepatic CD4 + T cells, p \xa0=\u20090.0003; 9.33\u2009±\u20094.03% vs. 22.55\u2009±\u20097.47% IFN-γ + in hepatic CD8 + T cells, p \xa0=\u20090.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4\u2009±\u200947.93 vs. 229.8\u2009±\u200945.86\u2009μmol/L total bilirubin, p \xa0=\u20090.01) 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.