Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats
Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats
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DOI：
10.1002/art.33321
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Breban, Maxime
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文献类型：
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作者：
Glatigny, Simon;Fert, Ingrid;Breban, Maxime
目的HLAB27/人β2-微球蛋白转基因(B27-转基因)大鼠是一种脊柱炎(SpA)动物模型，在常规条件下可诱发自发性结肠炎和关节炎。在B27转基因大鼠的炎症发展过程中，CD4+T细胞起关键作用。本研究旨在研究该模型中CD4+T细胞的表型特征，并确定树突状细胞(DC)是否诱导促炎T细胞。方法：研究方法。用流式细胞仪分析引流炎症部位的大鼠淋巴结(LNS)中的CD4+T细胞的表型。免疫组织化学染色检测大鼠关节内产生白介素17(IL-17)的细胞。将B27转基因大鼠或对照组(转HLAB7或非转基因大鼠)的DC与对照的CD4+T细胞共培养，并用抗T细胞受体α/β刺激。结果。从B27转基因大鼠的肠系膜和髓窝LN中扩增产生IL-17A-和肿瘤坏死因子α(TNFα)的CD4+T细胞。与Th1或Treg细胞相比，Th17细胞的积累与疾病的发展相关。B27转基因大鼠关节中可检测到IL-17阳性单个核细胞，而对照大鼠关节中未检测到IL-17阳性细胞。最后，体外共培养表明，B27转基因大鼠的DC优先诱导和扩增Th17细胞，这一过程可能涉及共刺激分子的缺陷结合。结论。我们的发现表明，在B27转基因大鼠中，扩增的CD4+T细胞表现出以IL-17A和肿瘤坏死因子α产生为特征的致炎Th17表型。此外，这一群体优先由B27转基因大鼠的DC诱导。这些数据表明，在这种SpA模型中，Th17细胞的诱导是可能的致病机制。然而，它们的致病作用仍需发挥。
Objective HLAB27/human beta 2-microglobulintransgenic (B27-transgenic) rats, a model of spondylarthritis (SpA), develop spontaneous colitis and arthritis under conventional conditions. CD4+ T cells are pivotal in the development of inflammation in B27-transgenic rats. This study was undertaken to characterize the phenotype of CD4+ T cells in this model and to determine whether dendritic cells (DCs) induce proinflammatory T cells. Methods. The phenotype of CD4+ T cells from rat lymph nodes (LNs) draining the sites of inflammation was analyzed by flow cytometry. Immunostaining was used to detect interleukin-17 (IL-17)-producing cells in the rat joints. DCs from B27-transgenic or control rats (transgenic for HLA-B7 or nontransgenic) were cocultured with control CD4+ T cells and stimulated with anti-T cell receptor alpha/beta. Results. IL-17A-and tumor necrosis factor alpha (TNF alpha)-producing CD4+ T cells were expanded in mesenteric and popliteal LNs from B27-transgenic rats. The accumulation of Th17 cells correlated with disease development, in contrast to Th1 or Treg cells. IL-17 positive mononuclear cells were detected in the arthritic joints of B27-transgenic rats but not in the joints of control rats. Finally, in vitro cocultures demonstrated that Th17 cells were preferentially induced and expanded by DCs from B27-transgenic rats, by a process that may involve defective engagement of costimulatory molecules. Conclusion. Our findings indicate that expanded CD4+ T cells in B27-transgenic rats exhibit a proinflammatory Th17 phenotype characterized by IL-17A and TNF alpha production. Furthermore, this population is preferentially induced by DCs from B27-transgenic rats. These data point toward an induction of Th17 cells as a possible pathogenic mechanism in this model of SpA. However, their pathogenic role still needs to be shown.