Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB.
Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB.
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DOI：
10.1084/jem.185.11.1897
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发表时间：
1997-06-02
期刊：
影响因子：
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通讯作者：
Ballard DW
中科院分区：
文献类型：
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作者：
Boothby MR;Mora AL;Scherer DC;Brockman JA;Ballard DW
核因子（NF）-κB/Rel家族转录因子的成员在胸腺选择期间和在T细胞抗原受体（TCR）连接后的成熟T淋巴细胞中被诱导。尽管有这些发现，单个NF-κB/Rel基因的破坏揭示了成熟T细胞发育中没有内在缺陷，这可能反映了功能冗余。为了避免这种可能性，靶向T细胞谱系以表达IκBα的反式显性形式，其组成性抑制多种NF-κB/Rel蛋白的活性。表达该抑制剂的转基因细胞表现出显著的增殖缺陷，这不能通过添加外源性白细胞介素-2来逆转。此外，与对照相比，脾细胞的促有丝分裂刺激导致转基因T细胞的凋亡增加。除了解除调节的T细胞生长和存活之外，转基因表达损害正常T细胞群体的发育，如由TCR hi CD 8单阳性胸腺细胞的数量减少所证明的。这种缺陷在外周显著扩增，并伴随着CD 4 + T细胞的减少。综上所述，这些体内研究结果表明，NF-κB/Rel信号通路包含对建立正常T细胞亚群至关重要的代偿组分。
Members of the nuclear factor (NF)-κB/Rel family transcription factors are induced during thymic selection and in mature T lymphocytes after ligation of the T cell antigen receptor (TCR). Despite these findings, disruption of individual NF-κB/Rel genes has revealed no intrinsic defect in the development of mature T cells, perhaps reflecting functional redundancy. To circumvent this possibility, the T cell lineage was targeted to express a trans-dominant form of IκBα that constitutively represses the activity of multiple NF-κB/Rel proteins. Transgenic cells expressing this inhibitor exhibit a significant proliferative defect, which is not reversed by the addition of exogenous interleukin-2. Moreover, mitogenic stimulation of splenocytes leads to increased apoptosis of transgenic T cells as compared with controls. In addition to deregulated T cell growth and survival, transgene expression impairs the development of normal T cell populations as evidenced by diminished numbers of TCRhi CD8 single-positive thymocytes. This defect was significantly amplified in the periphery and was accompanied by a decrease in CD4+ T cells. Taken together, these in vivo findings indicate that the NF-κB/Rel signaling pathway contains compensatory components that are essential for the establishment of normal T cell subsets.