Cutting edge:: Ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis
Cutting edge:: Ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.172.8.4686
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发表时间：
2004-04-15
影响因子：
4.4
通讯作者：
Miller, SD
中科院分区：
文献类型：
--
作者：
Kohm, AP;Williams, JS;Miller, SD
糖皮质激素诱导的TNFR（GITR）在静息的CD 4（+）CD 25（+）T调节（T-R）细胞上以高水平表达，并调节其抑制性表型。因此，我们表明，抗GITR mAb治疗蛋白脂质蛋白139-151诱导的实验性自身免疫性脑脊髓炎的SJL小鼠显著加剧了临床疾病的严重程度和CNS炎症，并诱导Ag特异性T细胞增殖和细胞因子产生水平升高。有趣的是，T-R细胞的先前消耗未能导致加重的实验性自身免疫性脑脊髓炎，这表明抗GITR mAb治疗的替代靶标。重要的是，初始CD 4（+）CD 25（-）T细胞以激活依赖性方式上调GITR表达，抗GITR mAb处理在体内和体外不存在TR细胞的情况下增强了CD 4（+）T细胞激活、增殖和细胞因子产生的水平。总之，这些发现表明GITR具有双重功能作用，因为GITR交联既使TR细胞失活又增加CD 4（+）CD 25（-）T细胞效应子功能，从而增强T细胞免疫。
The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4(+)CD25(+) T regulatory (T-R) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139-151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of T-R cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4(+) CD25(-) T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4(+) T cell activation, proliferation, and cytokine production in the absence of TR cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates TR cells and increases CD4(+) CD25(-) T cell effector function, thus enhancing T cell immunity.