Disruption of diacylglycerol metabolism impairs the induction of T cell anergy
Disruption of diacylglycerol metabolism impairs the induction of T cell anergy
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DOI：
10.1038/ni1400
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发表时间：
2006-11-01
影响因子：
30.5
通讯作者：
Zhong, Xiao-Ping
中科院分区：
文献类型：
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作者：
Olenchock, Benjamin A.;Guo, Rishu;Zhong, Xiao-Ping
无反应性T细胞改变了甘油二酯的代谢，但这种改变的代谢是否在诱导T细胞无反应性中具有致病作用尚不清楚。为了测试二酰基甘油代谢在T细胞无反应性中的重要性，我们操纵二酰基甘油激酶（DGK），其是终止二酰基甘油依赖性信号传导的酶。DGK-alpha的过表达导致T细胞受体信号传导的缺陷，这是无反应性的特征。我们产生了DGK-alpha缺陷小鼠，发现DGK-alpha缺陷T细胞具有更多的二酰基甘油依赖性T细胞受体信号传导。在DGK-α缺陷小鼠中，体内无反应性诱导受损。当在产生无能量的条件下刺激时，缺乏DGK-alpha或DGK-zeta的T细胞增殖并产生白细胞介素2。接受无反应性刺激的DGK-zeta缺陷T细胞中DGK-alpha活性的药理学抑制与接受CD 28共刺激的野生型T细胞增殖相似，并阻止无反应性诱导。我们的研究结果表明，调节甘油二酯代谢是至关重要的，在确定是否激活或无能energy-energy-after T细胞受体刺激。
Anergic T cells have altered diacylglycerol metabolism, but whether that altered metabolism has a causative function in the induction of T cell anergy is not apparent. To test the importance of diacylglycerol metabolism in T cell anergy, we manipulated diacylglycerol kinases ( DGKs), which are enzymes that terminate diacylglycerol-dependent signaling. Overexpression of DGK-alpha resulted in a defect in T cell receptor signaling that is characteristic of anergy. We generated DGK-alpha-deficient mice and found that DGK-alpha-deficient T cells had more diacylglycerol-dependent T cell receptor signaling. In vivo anergy induction was impaired in DGK-alpha-deficient mice. When stimulated in anergy-producing conditions, T cells lacking DGK-alpha or DGK-zeta proliferated and produced interleukin 2. Pharmacological inhibition of DGK-alpha activity in DGK-zeta-deficient T cells that received an anergizing stimulus proliferated similarly to wild-type T cells that received CD28 costimulation and prevented anergy induction. Our findings suggest that regulation of diacylglycerol metabolism is critical in determining whether activation or anergy ensues after T cell receptor stimulation.