Calcineurin B1 is essential for positive but not negative selection during thymocyte development
Calcineurin B1 is essential for positive but not negative selection during thymocyte development
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DOI：
10.1016/s1074-7613(04)00052-4
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发表时间：
2004-03-01
期刊：
影响因子：
32.4
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Neilson, JR;Winslow, MM;Crabtree, GR
在发育过程中，离散细胞的命运往往是由特定信号强度的变化造成的。这些看似模拟到数字的开关背后的机制还不清楚。在发育中的T淋巴细胞中，通过抗原受体的低强度信号导致正选择，而较强的信号导致负选择。通过删除胸腺细胞中编码钙调神经磷酸酶调节基因B1亚基的遗传位点，我们发现在正选择中对钙调神经磷酸酶是绝对需要的。相比之下，钙调神经磷酸酶的活性在几种负选择模型中是可有可无的。出乎意料的是，我们发现，在胸腺细胞发育的双阳性阶段，当发生选择时，从胸腺细胞中去除钙调神经磷酸酶活性会导致ERK激活效率低下。这些研究阐明了分级信号在T细胞发育中转化为离散结果的机制，并进一步表明钙调神经磷酸酶的发育作用可能有助于钙调神经磷酸酶抑制剂的免疫抑制。
During development, discrete cell fates often result from variation in the intensity of a particular signal. The mechanisms underlying these seemingly analog-to-digital switches are not understood. In developing T lymphocytes, low-intensity signals through the antigen receptor result in positive selection while more intense signals give rise to negative selection. By deleting the genetic locus encoding the regulatory B1 subunit of calcineurin specifically in thymocytes, we found an absolute requirement for calcineurin in positive selection. In contrast, calcineurin activity was dispensable in several models of negative selection. Unexpectedly, we found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs. These studies clarify the mechanism by which graded signals are converted to discrete outcomes in T cell development and further indicate that the developmental roles of calcineurin likely contribute to immunosuppression by calcineurin inhibitors.