title: Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells.
abstract: The "liver tolerance effect" has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A-pretreated mice, induced a regulatory phenotype in naive CD4(+) T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10-producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γ-secretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A-pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4(+) T cells. However, HCs from Con A-pretreated IFN regulatory factor 1(-/-) mice, which cannot respond to IFN-γ, as well as those from IFN-γ(-/-) mice failed to augment IL-10 production by CD4(+) T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Sven
authors.initials: S
authors.lastname: Burghardt
authors.forename: Annette
authors.initials: A
authors.lastname: Erhardt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Claass
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Thomas
authors.initials: T
authors.lastname: Jacobs
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Khalil
authors.initials: K
authors.lastname: Karimi
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019483:Disintegrins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006505:Hepatitis / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D000072100:Jagged-1 Protein; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D053515:Matrix Metalloproteinase 17 / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: D002135:Calcium-Binding Proteins; D019483:Disintegrins; D036341:Intercellular Signaling Peptides and Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016753:Interleukin-10; D007371:Interferon-gamma; D053515:Matrix Metalloproteinase 17