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

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of hepatology 2014-09, Vol.61 (3), p.594-599
Hauptverfasser: Carambia, Antonella, Freund, Barbara, Schwinge, Dorothee, Heine, Markus, Laschtowitz, Alena, Huber, Samuel, Wraith, David C, Korn, Thomas, Schramm, Christoph, Lohse, Ansgar W, Heeren, Joerg, Herkel, Johannes
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2014.04.027