title: Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium.
abstract: Chemokines and their receptors determine the distribution of leukocytes within tissues in health and disease. We have studied the role of the constitutive chemokine receptor CXCR4 and its ligand, stromal-derived factor-1 (SDF-1) in the perivascular accumulation of T cells in rheumatoid arthritis. We show that synovial T cells, which are primed CD45RO+CD45RBdull cells and consequently not expected to express constitutive chemokine receptors, have high levels of the chemokine receptor CXCR4. Sustained expression of CXCR4 was maintained on synovial T cells by specific factors present within the synovial microenvironment. Extensive screening revealed that TGF-beta isoforms induce the expression of CXCR4 on CD4 T cells in vitro. Depletion studies using synovial fluid confirmed an important role for TGF-beta1 in the induction of CXCR4 expression in vivo. The only known ligand for CXCR4 is SDF-1. We found SDF-1 on synovial endothelial cells and showed that SDF-1 was able to induce strong integrin-mediated adhesion of synovial fluid T cells to fibronectin and ICAM-1, confirming that CXCR4 expressed on synovial T cells was functional. These results suggest that the persistent induction of CXCR4 on synovial T cells by TGF-beta1 leads to their active, SDF-1-mediated retention in a perivascular distribution within the rheumatoid synovium.
authors.affiliation: Division of Immunity and Infection, Medical Research Council Center for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom. c.d.buckley@bham.ac.uk
authors.forename: C D
authors.initials: CD
authors.lastname: Buckley
authors.forename: N
authors.initials: N
authors.lastname: Amft
authors.forename: P F
authors.initials: PF
authors.lastname: Bradfield
authors.forename: D
authors.initials: D
authors.lastname: Pilling
authors.forename: E
authors.initials: E
authors.lastname: Ross
authors.forename: F
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: A
authors.initials: A
authors.lastname: Amara
authors.forename: S J
authors.initials: SJ
authors.lastname: Curnow
authors.forename: J M
authors.initials: JM
authors.lastname: Lord
authors.forename: D
authors.initials: D
authors.lastname: Scheel-Toellner
authors.forename: M
authors.initials: M
authors.lastname: Salmon
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000502:physiology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta