Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition
Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition
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DOI：
10.4049/jimmunol.177.11.8226
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
Zhu, Lingqiao;Ji, Fang;Zhang, Yanyun
T细胞介导的自身免疫的一个特征是自身反应性T细胞的持久性。然而，类风湿关节炎(RA)患者滑膜T细胞的维持方式仍有待阐明。我们发现RA患者滑膜关节的树突状细胞(DC)和组织表达的IDO水平高于健康献血者的DC。有趣的是，来自RA患者关节滑液(SF)的T细胞在自体或异体IDO阳性DC的反应下增殖，这一结果不受IDO抑制剂1-甲基-D-色氨酸(1-MT)的影响。相反，在同种异体或自体IDO阳性DC刺激的培养液中加入1-MT可显著促进健康供者外周血或RA患者外周血中T细胞的增殖。此外，我们还发现类风湿关节炎患者SF来源的T细胞中功能活跃的色氨酰-tRNA合成酶(TTS)显著升高，导致T细胞中色氨酸的储存增加，从而对IDO介导的色氨酸剥夺产生抵抗。抗干扰素-γ和肿瘤坏死因子-α的单抗可阻断RA-SF对T细胞TTS表达的促进作用。这些结果表明，T细胞对IDO介导的色氨酸剥夺的抵抗力是RA患者体内维持自身反应性T细胞的一种机制。具体地说，阻断T细胞中TTS表达的上调为开发治疗类风湿关节炎的新疗法提供了一条途径。
A hallmark of T cell-mediated autoimmunity is the persistence of autoreactive T cells. However, it remains to elucidate the manner in which synovial T cells are sustained in patients with rheumatoid arthritis (RA). We found that dendritic cells (DC) and tissues from the synovial joints of RA patients expressed higher levels of IDO than DC from healthy donors. Interestingly, T cells derived from the joint synovial fluid (SF) of RA patients proliferated in response to either autologous or allogeneic IDO-positive DC, an outcome that was not affected by the addition of IDO inhibitor 1-methyl-D-tryptophan (1-MT). In contrast, addition of 1-MT to the culture stimulated with allogeneic or autologous IDO-positive DC significantly enhanced the proliferation of T cells derived from peripheral blood of healthy donors or from peripheral blood of RA patients. Furthermore, we found that functionally active tryptophanyl-tRNA-synthetase (TTS) was significantly elevated in T cells derived from the SF of RA patients, leading to enhanced storage of tryptophan in T cells and to subsequent resistance to IDO-mediated deprivation of tryptophan. The RA SF enhancement of TTS expression in T cells was blocked by mAb to IFN-gamma and TNF-alpha. These results suggest that the resistance of T cells to IDO-mediated deprivation of tryptophan represents a mechanism by which autoreactive T cells are sustained in vivo in RA patients. Specifically, blocking of the up-regulation of TTS expression in T cells presents an avenue for development of a novel therapeutic approach to treatment of RA.