Igarashi Hanna, Cao Yujia, Iwai Hideyuki, Piao Jinhua, Kamimura Yosuke, Hashiguchi Masaaki, Amagasa Teruo, Azuma Miyuki
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Biochem Biophys Res Commun. 2008 May 16;369(4):1134-8. doi: 10.1016/j.bbrc.2008.03.024. Epub 2008 Mar 17.
Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25(-)CD4(+) effector (Teff) and CD25(+)CD4(+) regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4(+) T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4(+) T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.
糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）的激活能够共刺激CD25（-）CD4（+）效应T细胞（Teff）和CD25（+）CD4（+）调节性T细胞（Treg）；然而，GITR共刺激对Treg功能的影响仍存在争议。在本研究中，我们检测了GITR配体（GITRL）结合对CD4（+）T细胞各自功能的影响。GITRL-P815转染细胞有效地增强了Teff细胞抗CD3诱导的增殖和细胞因子产生。当提供外源性白细胞介素-2（IL-2）和更强的CD3刺激时，GITRL转染细胞也增强了Treg中的增殖和IL-10产生。Teff和Treg的同时GITRL共刺激将Treg的无反应状态转变为增殖状态，维持并增强其功能。因此，GITRL共刺激增强了CD4（+）T细胞的效应和调节功能。我们的结果表明，高度活化且比例增加的Treg会逆转GITRL共刺激在Teff中的免疫增强作用，这对于使用强效GITR激动剂的治疗应用可能存在问题。
