title: Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C.
abstract: OBJECTIVE
  Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions.
  
  
  METHODS
  Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C.
  
  
  RESULTS
  We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody.
  
  
  CONCLUSIONS
  Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany. bettina.langhans@ukb.uni-bonn.de
authors.forename: Bettina
authors.initials: B
authors.lastname: Langhans
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Marcell
authors.initials: M
authors.lastname: Louis
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Robert
authors.initials: R
authors.lastname: Hüneburg
authors.forename: Andrea
authors.initials: A
authors.lastname: Staratschek-Jox
authors.forename: Margarethe
authors.initials: M
authors.lastname: Odenthal
authors.forename: Steffen
authors.initials: S
authors.lastname: Manekeller
authors.forename: Michael
authors.initials: M
authors.lastname: Schepke
authors.forename: Jörg
authors.initials: J
authors.lastname: Kalff
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015415:Biomarkers; C508606:CXCL8 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016209:Interleukin-8
keywords: CCL2; Fibrogenesis; Foxp3; GARP; HCV; HSC; Hepatic stellate cells; Hepatitis C virus; IL-8; MMP2; RT-PCR; Regulatory T cells; T effector cells; TIMP1; Teffs; Tregs; alpha-SMA; alpha-smooth muscle actin; chemokine ligand 2; forkhead box P3; glycoprotein A repetitions predimonant; hepatitis C virus; mRNA; matrix metalloproteinases 2; messenger RNA; primary human hepatic stellate cells; real-time polymerase chain reaction; regulatory CD4(+) T cells; tissue inhibitor of metalloproteinases 1