title: Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils.
abstract: 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.
authors.affiliation: 1.825 Chalkstone Ave., Providence, RI 02908, USA. skatz@chartercare.org.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Licata
authors.forename: Cang T
authors.initials: CT
authors.lastname: Nguyen
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Burga
authors.forename: Vincent
authors.initials: V
authors.lastname: Falanga
authors.forename: N Joseph
authors.initials: NJ
authors.lastname: Espat
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Mitchell
authors.initials: M
authors.lastname: Thorn
authors.forename: Richard P
authors.initials: RP
authors.lastname: Junghans
authors.forename: Steven C
authors.initials: SC
authors.lastname: Katz
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002779:Cholestasis / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D007565:Jaundice / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: Treg; intrahepatic immunity; obstructive jaundice