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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.

Original publication

DOI

10.4049/jimmunol.165.6.3423

Type

Journal article

Journal

J immunol

Publication Date

15/09/2000

Volume

165

Pages

3423 - 3429

Keywords

Arthritis, Rheumatoid, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Line, Cell Movement, Cells, Cultured, Chemokine CXCL12, Chemokines, CXC, Endothelium, Vascular, Humans, Lymphocyte Activation, Receptors, CXCR4, Stromal Cells, Synovial Fluid, Synovial Membrane, T-Lymphocyte Subsets, Transforming Growth Factor beta