Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related with IL-12 signaling

TY - JOUR

T1 - Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related with IL-12 signaling

AU - Schwinge, Dorothee

AU - von Haxthausen, Franziska

AU - Quaas, Alexander

AU - Carambia, Antonella

AU - Otto, Benjamin

AU - Glaser, Fabian

AU - Höh, Benedikt

AU - Thiele, Nina

AU - Schoknecht, Tanja

AU - Huber, Samuel

AU - Steffens, Niklas

AU - Lohse, Ansgar W

AU - Herkel, Johannes

AU - Schramm, Christoph

N1 - Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PY - 2017/4

Y1 - 2017/4

N2 - BACKGROUND AND AIMS: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/ IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis.METHODS: Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2(-/-), DDC) or colitis (DSS) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg.RESULTS: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced pro-inflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to upregulation of the IL-12 receptor. Accordingly, IL-12 Receptor beta 2 knockout mice (IL-12rb2(-/-)) were able to maintain hepatic Treg functionality.CONCLUSIONS: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis.LAY SUMMARY: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular abilty to control immune responses; therefore, in vivo expansion of Treg might serve the treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases.

AB - BACKGROUND AND AIMS: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/ IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis.METHODS: Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2(-/-), DDC) or colitis (DSS) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg.RESULTS: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced pro-inflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to upregulation of the IL-12 receptor. Accordingly, IL-12 Receptor beta 2 knockout mice (IL-12rb2(-/-)) were able to maintain hepatic Treg functionality.CONCLUSIONS: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis.LAY SUMMARY: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular abilty to control immune responses; therefore, in vivo expansion of Treg might serve the treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases.

U2 - 10.1016/j.jhep.2016.12.001

DO - 10.1016/j.jhep.2016.12.001

M3 - SCORING: Journal article

C2 - 27965154

VL - 66

SP - 798

EP - 805

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 4

ER -