Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue
Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue
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DOI：
10.1002/art.11219
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Buckley, CD
中科院分区：
文献类型：
--
作者：
Bradfield, PF;Amft, N;Buckley, CD
目标。类风湿关节炎炎症浸润的一个特征是CD4和CD8 T淋巴细胞亚群在炎症滑膜内分离到不同的微结构域。本研究的目的是验证一般趋化因子和基质细胞衍生因子1 （SDF-1; CXCL12）特别负责产生这种独特的微区隔化的假设。我们研究了滑膜CD4/CD8 T细胞亚群如何与来自慢性炎症性滑膜病变和正常滑膜组织以及胎儿肺和成人皮肤的成纤维细胞共培养试验中相互作用。我们利用T细胞在成纤维细胞下迁移的能力（这一过程被称为伪表皮分化）作为滑膜组织内T细胞积累的体外标记。类风湿成纤维细胞样滑膜细胞（FLS）显示出支持高水平CD4和CD8 T细胞假上皮的独特能力。非类风湿FLS和胎儿肺成纤维细胞支持低水平的假上皮细胞，而皮肤源性成纤维细胞则不能。与CD4 T细胞相比，CD8 T细胞在成纤维细胞下的迁移效率更高，速度更快，这是CD8 T细胞固有的特征。类风湿成纤维细胞组成性地产生高水平的SDF-1 (CXCL12)，这在功能上是重要的，因为阻断研究显示T细胞假上皮细胞减少到非类风湿FLS的水平。类风湿成纤维细胞也组成性地产生高水平的血管细胞粘附分子1 (VCAM-1; CD106)，但这不会导致T细胞假上皮化，这与B细胞不同，B细胞需要SDF-1 (CXCL12)-CXCR4和CD49d-VCAM-1 （CD106）相互作用。重要的是，在离体检查中，只有类风湿FLS和类风湿衍生的滑液T细胞的组合支持假皮肤增生，证实了这些发现的体内相关性。这些研究表明，成纤维细胞（SDF-1的产生）和CD8/CD4 T细胞（CXCR4的表达）的内在特征是类风湿滑膜中T淋巴细胞积累的特征性模式的原因。这些发现提示，SDF-1/CXCR4配体/受体对可能在类风湿滑膜内T淋巴细胞积聚和定位中发挥重要的功能作用。
Objective. A characteristic feature of the inflammatory infiltrate in rheumatoid arthritis is the segregation of CD4 and CD8 T lymphocyte subsets into distinct microdomains within the inflamed synovium. The aim of this study was to test the hypothesis that chemokines in general and stromal cell-derived factor 1 (SDF-1; CXCL12) in particular are responsible for generating this distinctive microcompartmentalization.Methods. We examined how synovial CD4/CD8 T cell subsets interacted in coculture assays with fibroblasts derived from chronic inflammatory synovial lesions and normal synovial tissue as well as from fetal lung and adult skin. We used the ability of T cells to migrate beneath fibroblasts (a process called pseudoemperipolesis) as an in vitro marker of T cell accumulation within synovial tissue.Results. Rheumatoid fibroblast-like synoviocytes (FLS) displayed a unique ability to support high levels of CD4 and CD8 T cell pseudoemperipolesis. Nonrheumatoid FLS as well as fetal lung fibroblasts supported low levels of pseudoemperipolesis, while skin-derived fibroblasts were unable to do so. CD8 T cells migrated under fibroblasts more efficiently and at a higher velocity than CD4 T cells, a feature that was intrinsic to CD8 T cells. Rheumatoid fibroblasts constitutively produced high levels of SDF-1 (CXCL12), which was functionally important, since blocking studies showed reductions in T cell pseudoemperipolesis to levels seen in nonrheumatoid FLS. Rheumatoid fibroblasts also constitutively produced high levels of vascular cell adhesion molecule 1 (VCAM-1; CD106), but this did not contribute to T cell pseudoemperipolesis, unlike the case for B cells, which require SDF-1 (CXCL12)-CXCR4 and CD49d-VCAM-1 (CD106) interactions. Importantly, only combinations of rheumatoid FLS and rheumatoid-derived synovial fluid T cells supported pseudoemperipolesis when examined ex vivo, confirming the in vivo relevance of these findings.Conclusion. These studies demonstrate that features intrinsic to both fibroblasts (the production of SDF-1) and CD8/CD4 T cells (the expression of CXCR4) are responsible for the characteristic pattern of T lymphocyte accumulation seen in the rheumatoid synovium. These findings suggest that the SDF-1/CXCR4 ligand/receptor pair is likely to play an important functional role in T lymphocyte accumulation and positioning within the rheumatoid synovium.