PD-1 Protects Liver Damage by Suppressing IFN-γ Expression in T Cells in Infants and Neonatal Mice

Abstract

\n Background: Biliary atresia (BA) is a severe cholangiopathy resulting from virus-induced and immune-mediated injury of the biliary system. IFN-g, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death 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. Blockade of PD-1 increased IFN-g expression in CD4+ T and CD8+ T cells, suppressed bilirubin production and exacerbated liver immunopathology.Conclusions: PD-1 plays a protective role in infants with BA by suppressing IFN-g production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.