Zheng Yan, Zha Yuanyuan, Gajewski Thomas F
University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
EMBO Rep. 2008 Jan;9(1):50-5. doi: 10.1038/sj.embor.7401138.
The activation of T cells is tightly controlled by many positive and negative regulatory processes. This fine-tuning allows productive immunity to pathogens while minimizing the risk of autoimmunity. One negative regulatory mechanism is clonal anergy, which is a hyporesponsive state that occurs when T cells are activated through the T-cell antigen receptor in the absence of appropriate co-stimulatory signals. Recent studies have confirmed a crucial role for defective Ras activation in mediating this hyporesponsive state. Diminished Ras activation can, in part, be explained by the upregulated expression of diacylglycerol kinases (DGKs), which phosphorylate diacylglycerol and restrict Ras guanyl releasing protein 1 (RasGRP1)-dependent activation of Ras. Increased expression of DGKs is probably transcriptional and is accompanied by augmented expression of additional negative regulators, including the transcription factors early growth response (Egr) 2 and Egr3, and the E3 ubiquitin ligases known as gene related to anergy in lymphocytes (GRAIL) and Casitas B-cell lymphoma-b (Cbl-b). A model is emerging for how these factors are regulated to control T-cell responsiveness.
T细胞的激活受到许多正负调节过程的严格控制。这种精细调节在使自身免疫风险最小化的同时，确保对病原体产生有效的免疫反应。一种负调节机制是克隆失能，它是一种低反应状态，当T细胞在缺乏适当共刺激信号的情况下通过T细胞抗原受体被激活时就会出现。最近的研究证实，Ras激活缺陷在介导这种低反应状态中起关键作用。Ras激活减少部分可由二酰基甘油激酶（DGK）表达上调来解释，DGK可使二酰基甘油磷酸化，并限制Ras鸟苷释放蛋白1（RasGRP1）依赖的Ras激活。DGK表达增加可能是转录性的，同时还伴有其他负调节因子表达增加，包括转录因子早期生长反应（Egr）2和Egr3，以及淋巴细胞失能相关基因（GRAIL）和卡斯他B细胞淋巴瘤b（Cbl-b）等E3泛素连接酶。关于这些因子如何被调节以控制T细胞反应性的模型正在形成。
