OX40 signaling is involved in the autoactivation of CD4(+)CD28(-) T cells and contributes to the pathogenesis of autoimmune arthritis.
OX40 signaling is involved in the autoactivation of CD4(+)CD28(-) T cells and contributes to the pathogenesis of autoimmune arthritis.
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OX40 信号传导参与 CD4( )CD28(-) T 细胞的自身激活，并有助于自身免疫性关节炎的发病机制
DOI：
10.1186/s13075-017-1261-9
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发表时间：
2017-03-21
影响因子：
4.9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Jiang J;Liu C;Liu M;Shen Y;Hu X;Wang Q;Wu J;Wu M;Fang Q;Zhang X
CD 4 + CD 28 − T细胞在自身免疫性疾病（包括类风湿性关节炎（RA））中表现出自身反应潜力。在CD 28表达下调后，哪种共刺激分子在该亚群的激活中作为替代的第二信号起作用尚不清楚。肿瘤坏死因子受体超家族成员OX 40是T细胞活化的关键共刺激分子。本研究的目的是研究OX 40对自身免疫性关节炎中CD 4 + CD 28 − T细胞的共刺激作用。从RA患者和对照受试者中收集临床样本。胶原诱导的关节炎（CIA）诱导与胶原II型（CII）在DBA/1小鼠。通过流式细胞术检测CD 4 + CD 28 − OX 40 + T细胞亚群及其细胞因子产生。T细胞纯化后，在CIA小鼠中进行过继转移。通过体外和体内阻断实验确定OX 40的调节作用。OX 40和OX 40 L在RA患者和CIA小鼠中异常表达。进一步的分析表明，在RA患者和动物模型中，CD 4 + CD 28 − OX 40 + T细胞聚集。这些细胞产生更高水平的促炎细胞因子，并与受影响的个人的临床病理特征密切相关。CII特异性CD 4 + CD 28 − OX 40 + T细胞的连续转移显著加重了CIA小鼠的关节炎发展和关节病理学。此外，OX 40阻断显著降低促炎反应并改善关节炎发展。OX 40作为CD 4 + CD 28 − T细胞的另一种共刺激分子，在自身免疫性关节炎的发展中起致病作用，这表明它是RA免疫调节治疗的潜在靶点。本文的在线版本（doi：10.1186/s13075-017-1261-9）包含补充材料，可供授权用户使用。
CD4+CD28− T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4+CD28− T cells in autoimmune arthritis. Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4+CD28−OX40+ T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo. OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4+CD28−OX40+ T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4+CD28−OX40+ T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development. OX40 acts as an alternative costimulator of CD4+CD28− T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA. The online version of this article (doi:10.1186/s13075-017-1261-9) contains supplementary material, which is available to authorized users.