title: Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway.
abstract: Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T-cell responses towards tolerance. However, the role of LSECs in the regulation of T-cell-induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro-inflammatory Th1-cell differentiation in mice. Using in vitro co-culture systems and subsequent cytokine analysis, we showed that LSECs induced high amounts of the anti-inflammatory cytokine IL-10 in developing Th1 cells. These LSEC-stimulated Th1 cells had no pro-inflammatory capacity in vivo but instead actively suppressed an inflammatory Th1-cell-induced delayed-type hypersensitivity reaction. Blockage of IL-10 signaling in vivo inhibited immunosuppressive activity of LSEC-stimulated Th1 cells. We identified the Notch pathway as a mechanism how LSECs trigger IL-10 expression in Th1 cells. LSECs expressed high levels of the Delta-like and Jagged family of Notch ligands and induced expression of the Notch target genes hes-1 and deltex-1 in Th1 cells. Blockade of Notch signaling selectively inhibited IL-10 induction in Th1 cells by LSECs. Our findings suggest that LSEC-induced IL-10 expression in Th1 cells via the Notch pathway may contribute to the control of hepatic inflammatory immune responses by induction of a self-regulatory mechanism in pro-inflammatory Th1 cells.
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Rudolph
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Janke
authors.affiliation: Department of Hematopoiesis, Sanquin and Landsteiner Laboratory for Blood Research, Amsterdam, The Netherlands.
authors.forename: Derk
authors.initials: D
authors.lastname: Amsen
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D051880:Receptors, Notch; D016753:Interleukin-10
keywords: Hepatic immune tolerance; IL-10; Liver sinusoidal endothelial cells; Modulation of Th1 cells; Notch pathway