title: Interactions between Th1 cells and Tregs affect regulation of hepatic fibrosis in biliary atresia through the IFN-γ/STAT1 pathway.
abstract: Regulatory T cells (Tregs) and CD4+T helper (Th) cells have important roles in bile duct injury of biliary atresia (BA). However, their impacts on liver fibrosis are undefined. Between 2013 and 2016, 146 patients with various stages of BA were enrolled in this study. Peripheral blood, liver biopsy and lymph node samples were collected. Flow cytometry, magnetic cell sorting and immunostaining were used to characterize lymphocytes from BA patients. Deficiency of Tregs was observed along with increased Th1, Th2 and Th17 frequencies in the peripheral blood and livers of BA patients. The levels of peripheral and intrahepatic Th1 cells positively correlated with the stage of liver fibrosis. Furthermore, Th1 cells were located in close proximity to activated hepatic stellate cells (HSCs) and areas of fibrosis in BA livers. In culture, Th1 cells accelerated the proliferation and secretion of profibrogenic markers of HSCs through the IFN-γ/STAT1 pathway. Of note, Tregs blocked the Th1-stimulated effects on HSCs by inhibiting Th1-induced activation of STAT1. Consistent with the results of in vitro study, intrahepatic IFN-γ/STAT1 levels increased in relation to the severity of liver fibrosis in BA patients, and the altered balance between MMP2 and TIMP1 expressions in livers may contribute to increased deposition of extracellular matrix and fibrosis. Finally, to identify the effects of Th1 cells on Tregs, we demonstrated that Th1 cells upregulated the proportion of aTreg cells by secreting IFN-γ cytokine. Thus, aberrant Th1 immune responses in BA promote the proliferation and secretion of HSCs through the IFN-γ/STAT1 pathway. The regulation of HSCs by the interactions between Tregs and Th1 cells might be part of the mechanism underlying progressive liver fibrosis and may be a suitable target for therapy.
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Junkai
authors.initials: J
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.|Shanghai Institute of Pediatric Research, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D001656:Biliary Atresia / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D049109:Cell Proliferation; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma