CXCR4 and vascular cell adhesion molecule 1 are key chemokine/adhesion receptors in the migration of cytokine-activated T cells

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 64; no. 7; pp. 2137 - 2146
• Main Authors: Bryant, Jane, Ahern, David J., Brennan, Fionula M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Biological and medical sciences; Cell adhesion & migration; Cell Adhesion - drug effects; Cells, Cultured; Chemokines; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - immunology; Diseases of the osteoarticular system; Human Umbilical Vein Endothelial Cells; Humans; Integrin alpha4beta1 - metabolism; Interleukin-2 - pharmacology; Interleukin-6 - pharmacology; Leukocytes; Lymphocyte Function-Associated Antigen-1 - metabolism; Medical sciences; Receptors, CXCR4 - metabolism; Synovial Membrane - cytology; Synovial Membrane - drug effects; Synovial Membrane - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects; Vascular Cell Adhesion Molecule-1 - metabolism; Chemokine; Vascular cell adhesion molecule 1; Immunological investigation; Migration; Cytokine; T-Lymphocyte; Rheumatology
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.34394

Objective To examine the migratory properties of cytokine‐activated T (Tck) cells. Methods Tck cells were generated by culture of peripheral blood T cells in the presence of interleukin‐6 (IL‐6), tumor necrosis factor α, and IL‐2. Changes in cell surface phenotype were analyzed by flow cytometry. Chemotactic responsiveness was measured using in vitro chemotaxis assays and transendothelial migration through human umbilical vein endothelial cell monolayers. Levels of vascular cell adhesion molecule 1 (VCAM‐1) were measured by sandwich enzyme‐linked immunosorbent assay. Results Cytokine stimulation up‐regulated the expression of chemokine receptors and integrins on Tck cells, including CXCR4, very late activation antigen 4 (VLA‐4), and lymphocyte function–associated antigen 1. Increased expression of CXCR4 and VLA‐4 integrin resulted in concentration‐dependent chemotaxis to their ligands, stromal cell–derived factor 1 (SDF‐1) and VCAM‐1, which could be selectively blocked using a specific CXCR4 inhibitor and antibodies against VLA‐4. Increased expression of VLA‐4 also resulted in increased transendothelial migration of Tck cells, which could be abrogated using blocking antibodies against VLA‐4. Tck cells also showed an increased chemotactic response to rheumatoid arthritis (RA) fibroblast‐like synoviocytes cultured in vitro, which could be blocked using inhibitors against VLA‐4 and CXCR4. Conclusion The activated phenotype of Tck cells results in increased migratory responsiveness to SDF‐1 and soluble VCAM‐1, which are among the chemokines and proteins found elevated in the RA synovial joint environment. Cytokine‐dependent activation may contribute to RA pathogenicity by promoting T cell recruitment to and retention in the joint, perpetuating the inflammatory cascade in RA.