Tumor Necrosis Factor Receptor Type I Expression of CD4+T Cells in Rheumatoid Arthritis Enables Them to Follow Tumor Necrosis Factor Gradients Into the Rheumatoid Synovium
Tumor Necrosis Factor Receptor Type I Expression of CD4+T Cells in Rheumatoid Arthritis Enables Them to Follow Tumor Necrosis Factor Gradients Into the Rheumatoid Synovium
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DOI：
10.1002/art.37927
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发表时间：
2013-06-01
影响因子：
--
通讯作者：
Wagner, Ulf
中科院分区：
文献类型：
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作者：
Rossol, Manuela;Schubert, Kristin;Wagner, Ulf
目的细胞因子肿瘤坏死因子（TNF）在类风湿关节炎（RA）的发病机制中起重要作用，但其作用机制尚未完全阐明。本研究旨在探讨TNF在RA患者滑膜关节中T细胞聚集和迁移中的作用。方法采用水平振荡切片机制备类风湿关节炎滑膜组织切片，并与荧光标记的CD4+ T细胞共孵育。通过荧光和共聚焦显微镜检测迁移。从组织中回收迁移的T细胞并分析表型。在Transwell实验中分析了RA患者的CD4+ T细胞响应于增加浓度的TNF的趋化性。结果RA患者CD4+ T细胞迁移入组织切片的数量显著高于健康对照组。迁移性CD4+ T细胞与非迁移性T细胞的不同之处在于它们增加了TNF受体I型（TNFRI）的表达，TNFRI在RA患者的一部分循环CD4+ T细胞上表达，但在对照组中则没有。还发现来自RA患者外周血的CD 4 + T细胞在体外沿着沿着TNF浓度梯度迁移。因此，TNF或TNFRI的阻断几乎消除了滑膜组织中的体外T细胞迁移。结论TNF与TNFRI的相互作用是T细胞在滑膜组织中迁移的关键，提示TNF与TNFRI的相互作用可能是T细胞向滑膜组织迁移的关键。
Objective The cytokine tumor necrosis factor (TNF) plays a central role in the pathogenesis of rheumatoid arthritis (RA), but its disease-specific effector mechanisms have not been fully elucidated. This study was undertaken to investigate the role of TNF in T cell accumulation and migration in the synovitic joints of RA patients. Methods Vital tissue sections from rheumatoid synovium were generated using a horizontally oscillating microtome and were coincubated with fluorescence-labeled CD4+ T cells. Migration was detected by fluorescence and confocal microscopy. Migrating T cells were recovered from the tissue and analyzed for phenotype. Chemotaxis of CD4+ T cells from RA patients in response to increasing concentrations of TNF was analyzed in Transwell experiments. Results CD4+ T cells from RA patients migrated into the tissue sections in significantly higher numbers than T cells from healthy controls. Migrating CD4+ T cells differed from nonmigrating ones in their increased expression of TNF receptor type I (TNFRI), which was expressed on a fraction of circulating CD4+ T cells from RA patients, but not from controls. CD4+ T cells from the peripheral blood of RA patients were also found to migrate along TNF concentration gradients ex vivo. Accordingly, blockade of either TNF or TNFRI nearly abrogated in vitro T cell migration in synovial tissue. Conclusion Our findings indicate that the interaction of TNF with TNFRI is pivotal for T cell migration in synovial tissue in vitro, and thereby suggest a relevant role of the cytokine for in vivo T cell trafficking to synovitic joints.