Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils

Intrahepatic inflammation and liver T cell dysfunction due to obstructive jaundice are both ameliorated through abrogation of PD‐1 expression. Biliary obstruction is a common clinical problem that is associated with intrahepatic inflammation and impaired immunity. PD‐1 is well known to mediate T cell dysfunction but has been reported to promote and attenuate acute inflammation in various injury models. With the use of a well‐established murine model of BDL, we studied the effects of intrahepatic PD‐1 expression on LTC function, inflammation, and cholestasis. Following BDL, PD‐1 expression increased significantly among LTCs. Increased PD‐1 expression following BDL was associated with decreased LTC proliferation and less IFN‐γ production. Elimination of PD‐1 expression resulted in significantly improved proliferative capacity among LTC following BDL, in addition to a more immunostimulatory cytokine profile. Not only was LTC function rescued in PD‐1−/− mice, but also, the degrees of biliary cell injury, cholestasis, and inflammation were diminished significantly compared with WT animals following BDL. PD‐1‐mediated acute inflammation following BDL was associated with expansions of intrahepatic neutrophil and Th17 cell populations, with the latter dependent on IL‐6. PD‐1 blockade represents an attractive strategy for reversing intrahepatic immunosuppression while limiting inflammatory liver damage.