Rincón M, Whitmarsh A, Yang D D, Weiss L, Dérijard B, Jayaraj P, Davis R J, Flavell R A
Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
J Exp Med. 1998 Nov 16;188(10):1817-30. doi: 10.1084/jem.188.10.1817.
The extracellular signal-regulated kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways are triggered upon ligation of the antigen-specific T cell receptor (TCR). During the development of T cells in the thymus, the ERK pathway is required for differentiation of CD4(-)CD8(-) into CD4(+)CD8(+) double positive (DP) thymocytes, positive selection of DP cells, and their maturation into CD4(+) cells. However, the ERK pathway is not required for negative selection. Here, we show that JNK is activated in DP thymocytes in vivo in response to signals that initiate negative selection. The activation of JNK in these cells appears to be mediated by the MAP kinase kinase MKK7 since high levels of MKK7 and low levels of Sek-1/MKK4 gene expression were detected in thymocytes. Using dominant negative JNK transgenic mice, we show that inhibition of the JNK pathway reduces the in vivo deletion of DP thymocytes. In addition, the increased resistance of DP thymocytes to cell death in these mice produces an accelerated reconstitution of normal thymic populations upon in vivo DP elimination. Together, these data indicate that the JNK pathway contributes to the deletion of DP thymocytes by apoptosis in response to TCR-derived and other thymic environment- mediated signals.
细胞外信号调节激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）通路在抗原特异性T细胞受体（TCR）连接后被激活。在胸腺中T细胞发育过程中，ERK通路对于CD4(-)CD8(-)分化为CD4(+)CD8(+)双阳性（DP）胸腺细胞、DP细胞的阳性选择以及它们成熟为CD4(+)细胞是必需的。然而，ERK通路对于阴性选择并非必需。在此，我们表明JNK在体内DP胸腺细胞中被激活，以响应启动阴性选择的信号。这些细胞中JNK的激活似乎由丝裂原活化蛋白激酶激酶MKK7介导，因为在胸腺细胞中检测到高水平的MKK7和低水平的Sek-1/MKK4基因表达。使用显性负性JNK转基因小鼠，我们表明抑制JNK通路可减少体内DP胸腺细胞的缺失。此外，这些小鼠中DP胸腺细胞对细胞死亡的抗性增加，在体内消除DP后可加速正常胸腺群体的重建。总之，这些数据表明JNK通路通过凋亡响应TCR衍生的和其他胸腺环境介导的信号，促进DP胸腺细胞的缺失。
