Mor Adi, Keren Gad, Kloog Yoel, George Jacob
Cardiovascular Research Center, Department of Cardiology, Tel Aviv Sourasky Medical Center, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Eur J Immunol. 2008 Jun;38(6):1493-502. doi: 10.1002/eji.200838292.
Naturally occurring regulatory T cells (Treg) driven by their transcriptional controller Foxp3 are compromised in immune-mediated disorders and confer protection when adoptively transferred. We examined the Ras-inhibitory effect on functional determinants of Treg in vivo and in vitro. Ras was inhibited in Jurkat T cells by transfection with a dominant-negative form of Ras, or by shRNA for N-Ras, K-Ras, and H-Ras, or by farnesylthiosalycylic acid, a small-molecule inhibitor. Except for H-Ras transduction with shRNA, each inhibitory mode increased expression of Foxp3 and nuclear factor of activated T cell proteins, and surface expression of CD25. Ras inhibition in PBMC and spleen-derived lymphocytes reproduced these findings. The heightened Foxp3 expression reflected both increased basal cellular protein and peripheral conversion of non-Treg to Treg. Ras inhibition enhanced Treg-induced suppression; thus, when adoptively transferred to mice, Ras-inhibited Treg reduced the incidence of diabetes. Inhibition of Foxp3 by respective siRNA reversed the enhancement. Thus, inhibition of the N- or K-Ras isoform triggers an anti-inflammatory effect by up-regulating, via Foxp3 elevation, the numbers and functional suppressive properties of Treg.
由转录调控因子Foxp3驱动的天然调节性T细胞（Treg）在免疫介导的疾病中功能受损，而在过继转移时则具有保护作用。我们在体内和体外研究了Ras对Treg功能决定因素的抑制作用。通过转染显性负性形式的Ras、针对N-Ras、K-Ras和H-Ras的短发夹RNA（shRNA）或小分子抑制剂法尼基硫代水杨酸，在Jurkat T细胞中抑制Ras。除了用shRNA转导H-Ras外，每种抑制方式均增加了Foxp3和活化T细胞核因子蛋白的表达以及CD25的表面表达。在PBMC和脾源性淋巴细胞中抑制Ras重现了这些发现。Foxp3表达的升高反映了基础细胞蛋白的增加以及非Treg向Treg的外周转化。Ras抑制增强了Treg诱导的抑制作用；因此，当过继转移到小鼠体内时，Ras抑制的Treg降低了糖尿病的发病率。用相应的小干扰RNA（siRNA）抑制Foxp3可逆转这种增强作用。因此，抑制N-Ras或K-Ras亚型可通过上调Foxp3，增加Treg的数量和功能抑制特性，从而触发抗炎效应。
