Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells
Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells
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DOI：
10.1002/eji.200838167
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发表时间：
2008-08-01
影响因子：
5.4
通讯作者：
Ishii, Naoto
中科院分区：
文献类型：
--
作者：
Chen, Shuming;Ndhlovu, Lishomwa C.;Ishii, Naoto
不变自然杀伤T（iNKT）细胞是具有不变TCR的尖端T细胞的特殊亚群，其识别由CD 1d呈递的α-半乳糖基神经酰胺（α-GalCer）。除了在用α-GalCer刺激时通过不变TCR的信号之外，共刺激信号，例如通过CD 28和OX 40的信号，对于iNKT细胞的完全活化是必不可少的。在这项研究中，我们研究了一个众所周知的共刺激分子，糖皮质激素诱导的TNF受体（GITR），对银诱导的iNKT细胞活化的功能。出乎意料的是，激动性mAb DTA-1对GITR的参与抑制了iNKT细胞在α-GalCer刺激后的增殖和细胞因子产生。此外，仅在银引发阶段iNKT细胞中的GITR信号就足以抑制iNKT细胞活化。与这些结果一致，GITR缺陷型iNKT细胞在体外和体内均显示出在α-GalCer刺激后增强的增殖和增加的细胞因子产生。此外，α-GalCer的体内施用在GITR缺陷型小鼠中比在野生型小鼠中更有效地抑制肿瘤转移。总的来说，GITR在Ag诱导的iNKT细胞活化中起共抑制作用。
Invariant natural killer T (iNKT) cells are a special subset of tip T cells with invariant TCR, which recognize a-galactosylceramide (a-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with (x-GalCer, costimulatory signals, such as signals through CD28 and OX40, are indispensable for full activation of iNKT cells. In this study, we investigated the functions of a well-known costimulatory molecule, glucocorticoid-induced TNF receptor (GITR), on Ag-induced iNKT cell activation. Unexpectedly, engagement of GITR by agonistic mAb DTA-1 suppressed proliferation and cytokine production of iNKT cells upon (x-GalCer stimulation. in addition, GITR signals in iNKT cells during only the Ag-priming phase was sufficient to inhibit the iNKT cell activation. Consistent with these results, the GITR-deficient iNKT cells showed enhanced proliferation and increased cytokine production upon alpha-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of alpha-GalCer suppressed tumor metastasis more efficiently in GITR-deficient mice than in wild-type mice. Collectively, GITR plays a co-inhibitory role in Ag-induced iNKT cell activation.