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

• Published in: Journal of hepatology Vol. 61; no. 3; pp. 594 - 599
• Main Authors: 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: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2014
• Subjects: Animals; Antigen presentation; Autoimmunity; Cell Communication - drug effects; Cell Differentiation - drug effects; Cells, Cultured; Dendritic Cells - drug effects; Dendritic Cells - pathology; Endothelium - drug effects; Endothelium - pathology; Forkhead Transcription Factors - metabolism; Gastroenterology and Hepatology; Hepatic tolerance; In Vitro Techniques; Interleukin-2 Receptor alpha Subunit - metabolism; Kupffer Cells - drug effects; Kupffer Cells - pathology; Liver - drug effects; Liver - pathology; Liver sinusoidal endothelial cells; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Models, Animal; Regulatory T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; TGF-β; Transforming Growth Factor beta - pharmacology; Autoimmunity; Latency-associated peptide; Antigen presentation; Dendritic cells; Hepatic tolerance; Tregs; Kupffer cells; EAE; liver sinusoidal endothelial cells; Myelin basic protein; GFP; regulatory T cells; experimental autoimmune encephalomyelitis; DCs; glycoprotein-A repetitions predominant; Green fluorescent protein; GARP; TGF-β; KCs; LAP; MBP; LSECs; Liver sinusoidal endothelial cells; Regulatory T cells
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2014.04.027

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.