Nishioka Tomohisa, Nishida Emi, Iida Ryuji, Morita Akimichi, Shimizu Jun
Section of Immunology, Department of Mechanism of Aging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan.
Immunol Lett. 2008 Dec 22;121(2):97-104. doi: 10.1016/j.imlet.2008.09.003. Epub 2008 Oct 18.
CD4(+)Foxp3(+) regulatory T cells (Treg cells) play an important role in maintaining self-tolerance as suppressive/regulatory CD4 T cells. In vitro analyses have revealed the characteristics of Treg cells, that is, hyporesponsiveness when stimulated via TCR in the presence of splenic APC. In this study, we report a new mAb, G3c, which can induce the expansion of Treg cells stimulated with anti-CD3 Ab along with splenic APC, the culture conditions in which Treg cells exhibit hyporesponsiveness. Surprisingly, G3c mAb recognized glucocorticoid-induced TNFR family-related proteins (GITR). G3c mAb had stronger co-stimulatory activity for both Treg cells and responder T cells than another anti-GITR Ab (DTA1) in vitro. The in vivo administration of G3c increased the number of Treg cells and had less effect in inducing anti-tumor immunity in normal mice, although G3c had some anti-tumor effect on non-Treg cells in the absence of Treg cells in vivo, in contrast to the anti-tumor therapeutic effect of DTA1 in normal mice. Therefore, we need to know that the manipulation of immune responses with the use of anti-GITR Abs results from a balance between co-stimulatory effects on Treg cells and on responder cells, and we must aim at a narrow window leading to the therapeutic effects.
CD4(+)Foxp3(+)调节性T细胞（Treg细胞）作为抑制性/调节性CD4 T细胞在维持自身耐受中发挥重要作用。体外分析揭示了Treg细胞的特征，即在脾细胞抗原呈递细胞（APC）存在的情况下通过TCR刺激时反应低下。在本研究中，我们报告了一种新的单克隆抗体（mAb）G3c，它能诱导抗CD3抗体与脾细胞APC共同刺激的Treg细胞扩增，而在这种培养条件下Treg细胞表现出反应低下。令人惊讶的是，G3c单克隆抗体识别糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白（GITR）。在体外，G3c单克隆抗体对Treg细胞和反应性T细胞的共刺激活性均强于另一种抗GITR抗体（DTA1）。在正常小鼠体内给予G3c可增加Treg细胞数量，且在诱导抗肿瘤免疫方面作用较小，尽管在体内不存在Treg细胞时G3c对非Treg细胞有一定抗肿瘤作用，这与DTA1在正常小鼠中的抗肿瘤治疗效果相反。因此，我们需要知道，使用抗GITR抗体操纵免疫反应是Treg细胞和反应性细胞共刺激作用之间平衡的结果，而且我们必须瞄准导致治疗效果的狭窄窗口。
