title: Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver.
abstract: Regulatory T cells (T(regs)) are found at sites of chronic inflammation where they mediate bystander and Ag-specific suppression of local immune responses. However, little is known about the molecular control of T(reg) recruitment into inflamed human tissues. We report that up to 18% of T cells in areas of inflammation in human liver disease are forkhead family transcriptional regulator box P3 (FoxP3)(+) T(regs). We isolated CD4(+)CD25(+)CD127(low)FoxP3(+) T(regs) from chronically inflamed human liver removed at transplantation; compared with blood-derived T(regs), liver-derived T(regs) express high levels of the chemokine receptors CXCR3 and CCR4. In flow-based adhesion assays using human hepatic sinusoidal endothelium, T(regs) used CXCR3 and alpha4beta1 to bind and transmigrate, whereas CCR4 played no role. The CCR4 ligands CCL17 and CCL22 were absent from healthy liver, but they were detected in chronically inflamed liver where their expression was restricted to dendritic cells (DCs) within inflammatory infiltrates. These DCs were closely associated with CD8 T cells and CCR4(+) T(regs) in the parenchyma and septal areas. Ex vivo, liver-derived T(regs) migrated to CCR4 ligands secreted by intrahepatic DCs. We propose that CXCR3 mediates the recruitment of T(regs) via hepatic sinusoidal endothelium and that CCR4 ligands secreted by DCs recruit T(regs) to sites of inflammation in patients with chronic hepatitis. Thus, different chemokine receptors play distinct roles in the recruitment and positioning of T(regs) at sites of hepatitis in chronic liver disease.
authors.affiliation: Centre for Liver Research, Institute of Biomedical Research, The University of Birmingham Medical School, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.forename: David R
authors.initials: DR
authors.lastname: Withers
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Shishir
authors.initials: S
authors.lastname: Shetty
authors.forename: Jehan
authors.initials: J
authors.lastname: Harki
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shaw
authors.forename: Bertus
authors.initials: B
authors.lastname: Eksteen
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006521:Hepatitis, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D054398:Receptors, CCR4 / Q000378:metabolism / Q000502:physiology*; D054367:Receptors, CXCR3 / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C515354:CCR4 protein, human; C515187:CXCR3 protein, human; D018836:Inflammation Mediators; D008024:Ligands; D054398:Receptors, CCR4; D054367:Receptors, CXCR3