Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells
Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells
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DOI：
10.4049/jimmunol.172.12.7306
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发表时间：
2004-06-15
影响因子：
4.4
通讯作者：
Azuma, M
中科院分区：
文献类型：
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作者：
Kanamaru, F;Youngnak, P;Azuma, M
糖皮质激素诱导的TNF受体（GITR）是TNF受体家族的一员，在CD25(+)CD4（+）调节性T细胞上优先高水平表达，并在这些细胞介导的外周耐受性中起关键作用。GITR也在常规CD4（+）和CD8(+) T细胞上表达，激活后表达迅速增强。在本报告中，我们发现GITR为CD25（+）和CD25(-) CD4(+) T细胞提供了一个有效的共刺激信号。在有限剂量的抗cd3刺激下，抗GITR单抗DTA-1或GITR配体转染诱导的GITR介导的刺激有效地增强了CD25(-)CD4（+）和CD25(+)CD4(+) T细胞的增殖。细胞周期进程的增强进一步证实了T细胞活化的增强；早期诱导活化Ags、CD69和CD25；细胞因子的产生，如IL-2、ifn - γ、IL-4和IL-10；抗cd3诱导的重定向细胞毒性；和细胞内信号，通过NF-kappaB成分的易位来评估。GITR共刺激显示出产生大量IL-10的强大能力，这导致对增强的增殖反应的反调节。我们的研究结果强调了GITR作为早期CD4(+) T细胞激活的有效和独特的共刺激剂的证据。
The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF receptor family, is expressed preferentially at high levels on CD25(+)CD4(+) regulatory T cells and plays a key role in the peripheral tolerance that is mediated by these cells. GITR is also expressed on conventional CD4(+) and CD8(+) T cells, and its expression is enhanced rapidly after activation. In this report we show that the GITR provides a potent costimulatory signal to both CD25(+) and CD25(-) CD4(+) T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR ligand transfectants efficiently augmented the proliferation of both CD25(-)CD4(+) and CD25(+)CD4(+) T cells under the limited dose of anti-CD3 stimulation. The augmentation of T cell activation was further confirmed by the enhanced cell cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine production, such as IL-2, IFN-gamma, IL-4, and IL-10; anti-CD3-induced redirected cytotoxicity; and intracellular signaling, assessed by translocation of NF-kappaB components. GITR costimulation showed a potent ability to produce high amounts of IL-10, which resulted in counter-regulation of the enhanced proliferative responses. Our results highlight evidence that GITR acts as a potent and unique costimulator for an early CD4(+) T cell activation.