title: Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury.
abstract: BACKGROUND
  Accumulating evidence suggests that Foxp3+ regulatory T (Treg) cells act as inhibitory mediators of inflammation; however, the in vivo mechanism underlying this protection remains elusive in liver diseases.
  
  
  OBJECTIVE
  To clarify the in vivo role of Foxp3+ Treg cells in liver fibrosis, we used the DEREG mouse, which expresses the diphtheria toxin receptor under control of the Foxp3 promoter, allowing for specific deletion of Foxp3+ Treg cells.
  
  
  METHODS
  Bile duct ligation-induced liver injury and fibrosis were assessed by histopathology, fibrogenic gene expression, and measurement of cytokine and chemokine levels.
  
  
  RESULTS
  Depletion of Foxp3+ Treg cells enhanced Th17 cell response as demonstrated by the increase of IL-17+ cells and related gene expressions including Il17f, Il17ra, and Rorgt in the fibrotic livers of DEREG mice. Of note, infiltration of CD8+ T cells and Cd8 gene expression was significantly increased in the livers of DEREG mice. Consistent with increased IL-17+ and CD8+ T cell responses, DEREG mice generated higher levels of inflammatory cytokines (TNF-α, IL-6, and IL-12p70) and chemokines (MCP-1, MIP-1α, and RANTES). These results were concordant with severity of liver fibrosis and hepatic enzyme levels (ALT and ALP).
  
  
  CONCLUSIONS
  The present findings demonstrate that Foxp3+ Treg cells inhibit the profibrogenic inflammatory milieu through suppression of pro-fibrogenic CD8+ and IL-17+ T cells.
authors.affiliation: Laboratory of Pathology, College of Veterinary Medicine (BK21 Plus Program), Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Roh
authors.forename: Surim
authors.initials: S
authors.lastname: Park
authors.forename: Chae Woong
authors.initials: CW
authors.lastname: Lim
authors.forename: Bumseok
authors.initials: B
authors.lastname: Kim
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D018414:CD8-Positive T-Lymphocytes; D002779:Cholestasis / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D053645:Interleukin-2 Receptor alpha Subunit