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*
Division of Immunity and Infection, Medical Research Council Center for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, United Kingdom;
Unite d’Immunologie Virale, Institut Pasteur, Paris, France
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-ß isoforms induce the expression of CXCR4 on CD4 T cells in vitro. Depletion studies using synovial fluid confirmed an important role for TGF-ß1 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-ß1 leads to their active, SDF-1-mediated retention in a perivascular distribution within the rheumatoid synovium.
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S. A. Luther, A. Bidgol, D. C. Hargreaves, A. Schmidt, Y. Xu, J. Paniyadi, M. Matloubian, and J. G. Cyster Differing Activities of Homeostatic Chemokines CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell Recruitment and Lymphoid Neogenesis J. Immunol., July 1, 2002; 169(1): 424 - 433. [Abstract] [Full Text] [PDF]
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A. Valenzuela-Fernandez, T. Planchenault, F. Baleux, I. Staropoli, K. Le-Barillec, D. Leduc, T. Delaunay, F. Lazarini, J.-L. Virelizier, M. Chignard, et al. Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4 J. Biol. Chem., May 3, 2002; 277(18): 15677 - 15689. [Abstract] [Full Text] [PDF]
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A. J. Grant, S. Goddard, J. Ahmed-Choudhury, G. Reynolds, D. G. Jackson, M. Briskin, L. Wu, S. G. Hubscher, and D. H. Adams Hepatic Expression of Secondary Lymphoid Chemokine (CCL21) Promotes the Development of Portal-Associated Lymphoid Tissue in Chronic Inflammatory Liver Disease Am. J. Pathol., April 1, 2002; 160(4): 1445 - 1455. [Abstract] [Full Text] [PDF]
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H. Braley-Mullen, K. Chen, Y. Wei, and S. Yu Role of TGF{beta} in Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice J. Immunol., December 15, 2001; 167(12): 7111 - 7118. [Abstract] [Full Text] [PDF]
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T. Nanki, K. Nagasaka, K. Hayashida, Y. Saita, and N. Miyasaka Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis J. Immunol., November 1, 2001; 167(9): 5381 - 5385. [Abstract] [Full Text] [PDF]
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D. C. Hargreaves, P. L. Hyman, T. T. Lu, V. N. Ngo, A. Bidgol, G. Suzuki, Y.-R. Zou, D. R. Littman, and J. G. Cyster A Coordinated Change in Chemokine Responsiveness Guides Plasma Cell Movements J. Exp. Med., July 2, 2001; 194(1): 45 - 56. [Abstract] [Full Text] [PDF]
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