title: Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells.
abstract: A subset of human regulatory T cells (Tregs) can secrete IFN-γ or IL-17, and thus share features of TH1 or TH17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for TH1-like and IL-6 for TH17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-γ and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-γ partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Adam S
authors.identifier: 0000-0002-3817-890X
authors.initials: AS
authors.lastname: Arterbery
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Awo
authors.initials: A
authors.lastname: Osafo-Addo
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Ontario MSG 1X8, Canada;
authors.forename: Yaron
authors.initials: Y
authors.lastname: Avitzur
authors.affiliation: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520;
authors.forename: Maria
authors.initials: M
authors.lastname: Ciarleglio
authors.affiliation: Yale Center for Analytic Sciences, Yale School of Public Health, New Haven, CT 06520;
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, Columbia University, New York, NY 10032;
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lobritto
authors.affiliation: Department of Pediatrics, Columbia University, New York, NY 10032;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany; and VIB Laboratory of Translational Immunomodulation, Biomedical Research Institute, Hasselt University, BE3590 Diepenbeek, Belgium.
authors.forename: Markus
authors.initials: M
authors.lastname: Kleinewietfeld
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520; udeme.ekong@yale.edu.
authors.forename: Udeme D
authors.identifier: 0000-0002-3312-112X
authors.initials: UD
authors.lastname: Ekong
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016031:Liver Transplantation; D008297:Male; D009000:Monocytes / Q000276:immunology*; D011183:Postoperative Complications / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators