Swainson Louise, Kinet Sandrina, Mongellaz Cedric, Sourisseau Marion, Henriques Telmo, Taylor Naomi
Institut de Génétique Moléculaire de Montpellier, France.
Blood. 2007 Feb 1;109(3):1034-42. doi: 10.1182/blood-2006-06-027912. Epub 2006 Oct 5.
The IL-7 cytokine promotes the survival of a diverse T-cell pool, thereby ensuring an efficient immune response. Moreover, IL-7 induces the proliferation of recent thymic emigrants (RTEs) in neonates. Here, we demonstrate that the survival and proliferative effects of IL-7 on human RTEs can be distinguished on the basis of dose as well as duration of IL-7 administration. A dose of 0.1 ng/mL IL-7 is sufficient to promote viability, whereas cell-cycle entry is observed only at doses higher than 1 ng/mL. Moreover, a short 1-hour exposure to high-dose IL-7 (10 ng/mL) induces long-term survival but continuous IL-7 exposure is necessary for optimal cell-cycle entry and proliferation. We find that distinct signaling intermediates are activated under conditions of IL-7-induced survival and proliferation; STAT5 tyrosine phosphorylation does not correlate with proliferation, whereas up-regulation of the glucose transporter Glut-1 as well as increased glucose uptake are markers of IL-7-induced cell cycle entry. Glut-1 is directly regulated by PI3K and, indeed, inhibiting PI3K activity abrogates IL-7-induced proliferation. Our finding that the survival and proliferation of RTEs are differentially modulated by the dose and kinetics of exogenous IL-7 has important implications for the clinical use of this cytokine.
白细胞介素-7（IL-7）细胞因子可促进多种T细胞群体的存活，从而确保有效的免疫反应。此外，IL-7可诱导新生儿近期胸腺迁出细胞（RTEs）的增殖。在此，我们证明，IL-7对人类RTEs的存活和增殖作用可根据IL-7给药的剂量以及持续时间来区分。0.1 ng/mL的IL-7剂量足以促进细胞活力，而仅在高于1 ng/mL的剂量下才观察到细胞进入细胞周期。此外，短时间（1小时）暴露于高剂量IL-7（10 ng/mL）可诱导长期存活，但最佳的细胞周期进入和增殖需要持续暴露于IL-7。我们发现，在IL-7诱导的存活和增殖条件下，不同的信号中间体被激活；信号转导和转录激活因子5（STAT5）酪氨酸磷酸化与增殖无关，而葡萄糖转运蛋白Glut-1的上调以及葡萄糖摄取增加是IL-7诱导细胞进入细胞周期的标志物。Glut-1直接受磷脂酰肌醇-3激酶（PI3K）调控，事实上，抑制PI3K活性可消除IL-7诱导的增殖。我们的研究发现，外源性IL-7的剂量和动力学对RTEs的存活和增殖具有不同的调节作用，这对该细胞因子的临床应用具有重要意义。
