Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Aoba-ku, Sendai, Japan.
J Biol Chem. 2011 Apr 1;286(13):11110-8. doi: 10.1074/jbc.M110.166694. Epub 2011 Feb 3.
Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4+ T cells is not well understood. Here, we demonstrate that T-cell receptor (TCR) activation down-regulates distal Runx1 transcription, resulting in a significant reduction of Runx1 protein. Interestingly, this down-regulation of distal Runx1 transcription appears to be mediated through a negative auto-regulatory mechanism, whereby Runx1 protein binds to a Runx consensus site in the distal promoter. Through the use of Runx1-overexpressing cells from transgenic mice, we demonstrate that interference with TCR-mediated Runx1 down-regulation inhibits IL-2 production and proliferation in activated CD4+ T cells. In contrast, using Runx1-deficient cells prepared from targeted mice, we show that the absence of Runx1 in unstimulated CD4+ T cells results in IL-2 derepression. In summary, we propose that high levels of Runx1 in resting CD4+ T cells functions negatively in the regulation of IL-2 transcription, and that TCR activation-mediated down-regulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production.
Runx1 转录因子在 T 细胞发育、分化和功能中发挥多种作用。然而，静止外周 CD4+T 细胞中高表达 Runx1 蛋白的调节机制和功能意义尚不清楚。在这里，我们证明 T 细胞受体 (TCR) 激活下调远端 Runx1 转录，导致 Runx1 蛋白显著减少。有趣的是，这种远端 Runx1 转录的下调似乎是通过负反馈自动调节机制介导的，其中 Runx1 蛋白结合到远端启动子中的 Runx 共有序列上。通过使用来自转基因小鼠的 Runx1 过表达细胞，我们证明干扰 TCR 介导的 Runx1 下调会抑制激活的 CD4+T 细胞中 IL-2 的产生和增殖。相比之下，使用靶向敲除小鼠制备的 Runx1 缺陷细胞，我们表明未刺激的 CD4+T 细胞中缺乏 Runx1 会导致 IL-2 表达失控。总之，我们提出静止 CD4+T 细胞中高水平的 Runx1 负调控 IL-2 转录，而 TCR 激活介导的 Runx1 下调涉及远端 Runx1 启动子的负反馈自动调节，并有助于 IL-2 的产生。
