title: Foxp3 promoter methylation impairs suppressive function of regulatory T cells in biliary atresia.
abstract: Biliary atresia (BA) is characterized by progressive inflammation of the biliary system leading to liver cirrhosis, necessitating liver transplantation in pediatric patients. Various cell types have been reported to participate in the proinflammatory response in rhesus rotavirus (RRV)-induced BA mouse models, including T helper (Th) 1, Th2, Th17, CD8+T cells, and natural killer cells. The immune suppressive regulatory T (Treg) cells, on the contrary, were reported not to function properly. The underlying mechanism is largely unknown. Focusing on the impaired suppressive function of Treg, we found methylation status of CpG islands within the Foxp3 promoter region of Treg cells in BA patients and murine models were both increased. Moreover, by injecting 5-aza-2'-deoxycytidine (Aza) as DNA-methylation inhibitor to RRV-infected mice, BA phenotypes were alleviated. Furthermore, Treg cells isolated from "RRV+Aza"-injected mice had better suppressive function than Treg cells from mice injected with RRV only, both in vivo and ex vivo. Thus we concluded that aberrant increased methylation status of "Foxp3 promoter" in Treg cells leads to impaired Treg suppressive function, exacerbating inflammatory injury in BA.
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Cao
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yong-Zhong
authors.initials: YZ
authors.lastname: Mao
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China tshaotao83@126.com.
authors.forename: Shao-Tao
authors.identifier: 0000-0002-1851-0610
authors.initials: ST
authors.lastname: Tang
mesh_terms: D000818:Animals; D001656:Biliary Atresia / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
keywords: Foxp3; Treg cells; methylation, IL-17+ Treg cells, biliary atresia