Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea.
Int Immunol. 2011 Sep;23(9):583-92. doi: 10.1093/intimm/dxr058. Epub 2011 Jul 12.
Naive peripheral CD4(+)CD25(-) T cells can be converted into Foxp3-expressing regulatory T cells under appropriate stimulation conditions. Considering that continuous exposure to antigens is one of the prerequisites for the differentiation and maintenance of Treg cells, we investigated whether preventing activation-induced cell death while providing continuous TCR stimulation could promote the expression of Foxp3 in murine naive CD4(+) T cells. Among the several anti-apoptotic agents tested, aurintricarboxylic acid (ATA) was found to induce the in vitro conversion of naive CD4(+) T cells into Foxp3(+) Treg cells with suppressive activity. Neutralizing studies with an antibody against transforming growth factor (TGF)-β revealed that ATA requires the presence of TGF-β to induce Foxp3 expression in naive CD4(+)CD25(-) T cells. Although ATA itself did not activate the Smad signaling pathway, it down-regulated the extracellular signal-regulated kinase and mammalian target of rapamycin signaling cascade in activated T cells. Lastly, combined exposure to ATA and TGF-β had a synergistic effect on the rate of induction and maintenance of Foxp3 expression. These results indicate that ATA could be exploited to efficiently prepare inducible regulatory T cells in vitro and may aid in more precisely identifying the specific signaling pathways that drive Foxp3 expression in T cells.
幼稚外周 CD4(+)CD25(-)T 细胞在适当的刺激条件下可被转化为 Foxp3 表达的调节性 T 细胞。鉴于持续暴露于抗原是 Treg 细胞分化和维持的前提之一，我们研究了在提供持续 TCR 刺激的同时防止激活诱导的细胞死亡是否能促进小鼠幼稚 CD4(+)T 细胞中 Foxp3 的表达。在测试的几种抗凋亡剂中，金顶侧耳酸（ATA）被发现可诱导体外幼稚 CD4(+)T 细胞向具有抑制活性的 Foxp3(+)Treg 细胞转化。用转化生长因子（TGF）-β的抗体进行的中和研究表明，ATA 诱导幼稚 CD4(+)CD25(-)T 细胞中 Foxp3 表达需要 TGF-β的存在。尽管 ATA 本身不能激活 Smad 信号通路，但它可下调活化 T 细胞中的细胞外信号调节激酶和哺乳动物雷帕霉素靶蛋白信号级联。最后，ATA 和 TGF-β的联合暴露对 Foxp3 表达的诱导和维持率具有协同作用。这些结果表明，ATA 可用于体外有效地制备诱导型调节性 T 细胞，并可能有助于更准确地确定驱动 T 细胞中 Foxp3 表达的特定信号通路。
