title: Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling.
abstract: 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.
  
  
  
  Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2-/-, DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg.
  
  
  
  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 an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL-12rb2-/-) were able to maintain hepatic Treg functionality.
  
  
  
  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.
  
  
  
  Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a 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. Data accession number: GSE 87898.
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: d.schwinge@uke.de.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Schwinge
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: von Haxthausen
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department for Pathology, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Carambia
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Glaser
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Höh
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Thiele
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schoknecht
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Steffens
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
authors.affiliation: Department of Medicine I., University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: cschramm@uke.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
mesh_terms: D000818:Animals; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508443:Il12rb2 protein, mouse; D007376:Interleukin-2; D053707:Receptors, Interleukin-12; D018664:Interleukin-12
keywords: IL-12 receptor; IL-2/IL-2Ab complex; Primary sclerosing cholangitis; Treg expansion