Buckley C D, Amft N, Bradfield P F, Pilling D, Ross E, Arenzana-Seisdedos F, Amara A, Curnow S J, Lord J M, Scheel-Toellner D, Salmon M
Division of Immunity and Infection, Medical Research Council Center for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom.
J Immunol. 2000 Sep 15;165(6):3423-9. doi: 10.4049/jimmunol.165.6.3423.
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.
趋化因子及其受体决定了白细胞在健康和疾病状态下在组织中的分布。我们研究了组成型趋化因子受体CXCR4及其配体基质细胞衍生因子-1（SDF-1）在类风湿关节炎中T细胞血管周围积聚中的作用。我们发现，滑膜T细胞是已致敏的CD45RO+CD45RBdull细胞，因此预计不会表达组成型趋化因子受体，但却有高水平的趋化因子受体CXCR4。滑膜微环境中存在的特定因子维持了滑膜T细胞上CXCR4的持续表达。广泛筛选显示，转化生长因子-β（TGF-β）亚型在体外可诱导CD4 T细胞表达CXCR4。利用滑液进行的去除研究证实了TGF-β1在体内诱导CXCR4表达中的重要作用。CXCR4唯一已知的配体是SDF-1。我们在滑膜内皮细胞上发现了SDF-1，并表明SDF-1能够诱导滑液T细胞通过整合素介导与纤连蛋白和细胞间黏附分子-1（ICAM-1）发生强烈黏附，这证实了滑膜T细胞上表达的CXCR4具有功能。这些结果表明，TGF-β1持续诱导滑膜T细胞表达CXCR4，导致它们通过SDF-1介导在类风湿滑膜的血管周围分布中被主动滞留。
