An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis.
An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis.
复制标题
核因子Kappab在促进双胸腺细胞凋亡中的重要作用。
DOI：
10.1084/jem.189.1.145
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发表时间：
1999-01-04
影响因子：
15.3
通讯作者：
Leiden, J M
中科院分区：
文献类型：
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作者：
Hettmann, T;DiDonato, J;Karin, M;Leiden, J M
为了研究核因子(NF)-κB在体内T细胞发育和活化中的作用，我们制造了在T细胞特异性CD2启动子和增强子（突变体[m] i -κB -α小鼠）的控制下表达超抑制突变型抑制剂κB-α (i -κB -α a32 /36)的转基因小鼠。mIκB-α小鼠胸腺细胞发育正常。然而，这些动物的外周CD8+ T细胞数量明显减少。在T细胞抗原受体交联后，mir - κ b -α胸腺细胞表现出明显的增殖缺陷，白细胞介素(IL)-2、IL-3和粒细胞/巨噬细胞集落刺激因子的产生显著减少。也许更出乎意料的是，在体内，来自mIκB-α小鼠的双阳性（CD4+CD8+； DP）胸腺细胞对α- cd3介导的细胞凋亡具有抗性。相反，它们对γ辐照诱导的细胞凋亡仍然敏感。α-CD3单抗对野生型DP胸腺细胞凋亡的影响是抗凋亡基因bcl-xL的表达水平显著降低。相比之下，经α-CD3处理后，DP胸腺细胞bcl-xL维持高水平表达。综上所述，这些结果证明了NF-κB在TCR参与后诱导细胞因子表达和T细胞增殖中的重要作用。此外，α- cd3介导的DP胸腺细胞凋亡需要NF-κB参与，其途径涉及抗凋亡基因bcl-xL的调控。
To examine the role of nuclear factor (NF)-κB in T cell development and activation in vivo, we produced transgenic mice that express a superinhibitory mutant form of inhibitor κB-α (IκB-αA32/36) under the control of the T cell–specific CD2 promoter and enhancer (mutant [m]IκB-α mice). Thymocyte development proceeded normally in the mIκB-α mice. However, the numbers of peripheral CD8+ T cells were significantly reduced in these animals. The mIκB-α thymocytes displayed a marked proliferative defect and significant reductions in interleukin (IL)-2, IL-3, and granulocyte/macrophage colony-stimulating factor production after cross-linking of the T cell antigen receptor. Perhaps more unexpectedly, double positive (CD4+CD8+; DP) thymocytes from the mIκB-α mice were resistant to α-CD3–mediated apoptosis in vivo. In contrast, they remained sensitive to apoptosis induced by γ-irradiation. Apoptosis of wild-type DP thymocytes after in vivo administration of α-CD3 mAb was preceded by a significant reduction in the level of expression of the antiapoptotic gene, bcl-xL. In contrast, the DP mIκB-α thymocytes maintained high level expression of bcl-xL after α-CD3 treatment. Taken together, these results demonstrated important roles for NF-κB in both inducible cytokine expression and T cell proliferation after TCR engagement. In addition, NF-κB is required for the α-CD3–mediated apoptosis of DP thymocytes through a pathway that involves the regulation of the antiapoptotic gene, bcl-xL.