Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells

• Published in: The Journal of immunology (1950) Vol. 196; no. 10; pp. 4040 - 4051
• Main Authors: Arterbery, Adam S, Osafo-Addo, Awo, Avitzur, Yaron, Ciarleglio, Maria, Deng, Yanhong, Lobritto, Steven J, Martinez, Mercedes, Hafler, David A, Kleinewietfeld, Markus, Ekong, Udeme D
• Format: Journal Article
• Language: English
• Published: United States 15.05.2016
• Subjects: Adolescent; Cells, Cultured; Child; Cytokines - metabolism; DNA Methylation; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Hepatitis, Autoimmune - etiology; Hepatitis, Autoimmune - immunology; Humans; Inflammation Mediators - metabolism; Liver Transplantation; Male; Monocytes - immunology; Postoperative Complications - immunology; T-Lymphocytes, Regulatory - immunology; Th1 Cells - immunology; Transplantation, Homologous
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1502276

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.