Deltex1 Is a Target of the Transcription Factor NFAT that Promotes T Cell Anergy
Deltex1 Is a Target of the Transcription Factor NFAT that Promotes T Cell Anergy
复制标题
DOI：
10.1016/j.immuni.2009.04.017
复制
发表时间：
2009-07-17
期刊：
影响因子：
32.4
通讯作者：
Lai, Ming-Zong
中科院分区：
文献类型：
--
作者：
Hsiao, Huey-Wen;Liu, Wen-Hsien;Lai, Ming-Zong
T细胞无反应性的分子过程还不完全清楚。Deltex 1（DTX 1）是一个生理功能未知的Notch靶标。Dtx 1是活化T细胞核因子（NFAT）的转录靶点，参与T细胞无能的发生。DTX 1蛋白在T细胞无能期间上调，并且Dtx 1的转基因表达减弱T细胞活化。DTX 1通过E3依赖性和E3非依赖性机制抑制T细胞活化。此外，DTX 1在缺乏Notch结合结构域的情况下抑制T细胞活化。重要的是，DTX 1调节两种无能量相关分子的表达，即生长停滞和DNA损伤诱导型45 β（Gadd 45 β）和Cbl-b。DTX 1与早期生长反应2（Egr-2）相互作用以优化Cbl-b的表达。此外，DTX 1的缺乏增强了T细胞活化，赋予了对无反应性诱导的抗性，增强了自身抗体的产生，并增加了炎症。因此，DTX 1代表调节T细胞无反应性的钙-NFAT信号传导的下游组分。
The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore represents a component downstream of calcium-NFAT signaling that regulates T cell anergy.