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首页> 外文期刊>Molecular and Cellular Biology >Expression of Constitutively Active IκBβ in T Cells of Transgenic Mice: Persistent NF-κB Activity Is Required for T-Cell Immune Responses
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Expression of Constitutively Active IκBβ in T Cells of Transgenic Mice: Persistent NF-κB Activity Is Required for T-Cell Immune Responses

机译：组成性活性IκBβ在转基因小鼠T细胞中的表达：持续的NF-κB活性是T细胞免疫反应所必需的

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The transcription factor NF-κB is normally sequestered in the cytoplasm by members of the IκB family, including IκBα, IκBβ, and the recently cloned IκB?. Upon cellular activation, these inhibitors are rapidly phosphorylated on two amino-terminal serines, ubiquitinated, and degraded by the 26S proteasome, releasing a functional NF-κB. To determine the importance of IκBβ in NF-κB regulation in T cells, we generated transgenic mice expressing a constitutively active IκBβ mutant (mIκBβ) under the control of the lck promoter. The transgene contains the two critical N-terminal serine residues mutated to alanines and therefore no longer susceptible to degradation upon cell activation. mIκBβ is unable to totally displace IκBα from RelA-containing complexes, thus allowing a transient activation of NF-κB upon T-cell stimulation. However, mIκBβ completely blocks NF-κB activity after IκBα degradation. In addition, as a consequence of this inhibition,ikba expression is down regulated, along with that of other NF-κB-regulated genes. These transgenic mice have a significant reduction in the peripheral T-cell population, especially CD8+ cells. The remaining T cells have impaired proliferation in response to phorbol 12-myristate 13-acetate plus phytohemagglutinin or calcium ionophore but not to anti-CD3/anti-CD28 costimulation. As a result of these alterations, transgenic animals present defects in immune responses such as delayed-type hypersensitivity and the generation of specific antibodies against T-cell-dependent antigens. These results show that in nonstimulated T cells, IκBβ cannot efficiently displace IκBα bound to RelA-containing complexes and that persistent NF-κB activity is required for proper T-cell responses in vivo.
机译：转录因子NF-κB通常被IκB家族的成员隔离在细胞质中，包括IκBα，IκBβ和最近克隆的IκBα。在细胞激活后，这些抑制剂在两个氨基末端的丝氨酸上迅速磷酸化，泛素化并被26S蛋白酶体降解，从而释放功能性NF-κB。为了确定IκBβ在T细胞中NF-κB调节中的重要性，我们生成了在 lck 启动子控制下表达组成型活性IκBβ突变体（mIκBβ）的转基因小鼠。转基因含有突变为丙氨酸的两个关键的N端丝氨酸残基，因此在细胞活化后不再易于降解。 mIκBβ无法完全从含RelA的复合物中置换IκBα，因此在T细胞刺激后允许NF-κB瞬时激活。但是，IκBα降解后，mIκBβ完全阻断了NF-κB的活性。此外，由于这种抑制作用， ikba 表达与其他NF-κB调控基因一起被下调。这些转基因小鼠的外周T细胞数量，特别是CD8 + 细胞明显减少。其余的T细胞响应佛波醇12-肉豆蔻酸酯13-乙酸酯加上植物血凝素或钙离子载体而损害了增殖，但没有抗CD3 /抗CD28共刺激。这些改变的结果是，转基因动物的免疫反应存在缺陷，例如迟发型超敏反应和针对T细胞依赖性抗原的特异性抗体的产生。这些结果表明，在未刺激的T细胞中，IκBβ无法有效置换与含RelA的复合物结合的IκBα，并且体内持续的NF-κB活性是体内适当的T细胞反应所必需的。

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