Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells
Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells
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DOI：
10.1111/j.1365-2567.2006.02459.x
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发表时间：
2006-12-01
期刊：
影响因子：
6.4
通讯作者：
Kwon, Byoung S.
中科院分区：
文献类型：
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作者：
Lee, Sun K.;Choi, Beom K.;Kwon, Byoung S.
据报道，糖皮质激素诱导的肿瘤坏死因子受体家族相关基因（GITR）在活化的T细胞和CD4（+）CD25（+）调节性T细胞（Treg）上表达。 GITR 触发的信号不仅可以中和 Treg 细胞的抑制作用，还可以增强效应 T 细胞的激活、增殖和细胞因子的产生。为了测试 GITR 在 2,4,6-三硝基苯磺酸 (TNBS) 诱导的结肠炎（粘膜炎症小鼠模型）中的作用，用激动性抗 GITR 单克隆抗体 (mAb) 治疗注射 TNBS 的 Balb/c 小鼠。与大鼠 IgG 治疗的小鼠相比，抗 GITR 治疗增加了死亡率。通常，当小鼠接受抗 GITR 治疗时，死亡发生在注射 TNBS 后 4 天内。在抗 GITR 治疗中幸存下来的小鼠的整个肠道都出现了严重的炎症。 CD4(+) T 消除可以保护小鼠免受结肠炎的影响；甚至抗 GITR 效果也不明显。相比之下，CD8(+) T 消除的保护作用低于 CD4(+) T 消除的保护作用。 GITR 的刺激增强了促炎细胞因子的产生，包括干扰素 (IFN)-γ、肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-6 和 IL-12。它还增强了体液反应，例如血清IgG(2b)和IgA水平，这完全依赖于CD4(+)T细胞。综上所述，这项研究表明，CD4(+) T 细胞上的 GITR 信号传导通过增强 1 型辅助性 T (Th1) 和 Th2 型反应，参与结肠炎的发生和进展。
The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.