title: TGF-β-dependent induction of CD4⁺CD25⁺Foxp3⁺ Tregs by liver sinusoidal endothelial cells.
abstract: OBJECTIVE
  CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) have a profound ability to control immune responses. We have previously shown that the liver is a major source of peripherally induced Tregs. Here, we investigate the liver cell types and molecular mechanisms responsible for hepatic Treg induction.
  
  
  METHODS
  To assess the Treg-inducing potential of liver resident antigen-presenting cell types, we studied the conversion of Foxp3(-) non-Tregs into Foxp3(+) Tregs induced by liver dendritic cells (DCs), liver sinusoidal endothelial cells (LSECs), or Kupffer cells (KCs). The dependency of Treg induction on TGF-β was tested in Treg conversion assays using T cells with reduced TGF-β sensitivity. The suppressive potential of liver cell-induced Tregs was assessed by an in vitro suppression assay and in vivo, in the model of experimental autoimmune encephalomyelitis (EAE).
  
  
  RESULTS
  All tested liver cell types were capable of inducing Foxp3(+) Tregs; however, LSECs were most efficient in inducing Tregs. Treg-induction was antigen-specific and depended on TGF-β. LSECs featured membrane-bound LAP/TGF-β and the anchor molecule GARP, which is required for tethering LAP/TGF-β to the cell membrane. LSEC-induced Tregs suppressed proliferation and cytokine secretion of effector T cells in vitro. LSEC-induced Tregs were also functional suppressors in vivo, as neuroantigen-specific Tregs induced by LSECs were able to suppress EAE.
  
  
  CONCLUSIONS
  We demonstrate that LSECs are the major liver cell type responsible for TGF-β dependent hepatic Treg induction. The extraordinary capacity of LSECs to induce Tregs was associated with their unique ability to tether TGF-β to their membrane.
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Carambia
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Freund
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Schwinge
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Heine
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Laschtowitz
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.affiliation: Cellular and Molecular Medicine, University of Bristol, Medical Sciences Building, Bristol BS8 1TD, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
authors.affiliation: Department of Neurology, TU München, Ismaninger Str. 22, D-81675 München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Electronic address: jherkel@uke.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D066298:In Vitro Techniques; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D023421:Models, Animal; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta
keywords: Antigen presentation; Autoimmunity; Hepatic tolerance; Liver sinusoidal endothelial cells; Regulatory T cells; TGF-β