TGF-β-dependent induction of CD4⁺CD25⁺Foxp3⁺ Tregs by liver sinusoidal endothelial cells

Antonella Carambia, Barbara Freund, Dorothee Schwinge, Markus Heine, Alena Laschtowitz, Samuel Huber, David Wraith, Thomas Korn, Christoph Schramm, Ansgar W Lohse, Joerg Heeren, Johannes Herkel

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

BACKGROUND & AIMS: 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.

Original languageEnglish
Pages (from-to)594-599
Number of pages6
JournalJournal of Hepatology
Volume61
Issue number3
Early online date2 May 2014
DOIs
Publication statusPublished - 1 Sep 2014

Keywords

  • Animals
  • Cell Communication
  • Cell Differentiation
  • Cells, Cultured
  • Dendritic Cells
  • Endothelium
  • Forkhead Transcription Factors
  • In Vitro Techniques
  • Interleukin-2 Receptor alpha Subunit
  • Kupffer Cells
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • Models, Animal
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Hepatic tolerance
  • Regulatory T cells
  • Autoimmunity
  • Liver sinusoidal endothelial cells
  • Antigen presentation
  • TGF-β

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