Boothby M R, Mora A L, Scherer D C, Brockman J A, Ballard D W
Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Exp Med. 1997 Jun 2;185(11):1897-907. doi: 10.1084/jem.185.11.1897.
Members of the nuclear factor (NF)-kappaB/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-kappaB/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 IkappaBalpha that constitutively represses the activity of multiple NF-kappaB/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-kappaB/Rel signaling pathway contains compensatory components that are essential for the establishment of normal T cell subsets.
核因子（NF）-κB/Rel家族转录因子成员在胸腺选择过程中以及T细胞抗原受体（TCR）连接后在成熟T淋巴细胞中被诱导。尽管有这些发现，但单个NF-κB/Rel基因的破坏并未揭示成熟T细胞发育中的内在缺陷，这可能反映了功能冗余。为了规避这种可能性，靶向T细胞谱系以表达一种组成型抑制多种NF-κB/Rel蛋白活性的反式显性形式的IκBα。表达这种抑制剂的转基因细胞表现出明显的增殖缺陷，添加外源性白细胞介素-2并不能逆转这种缺陷。此外，与对照相比，脾细胞的有丝分裂原刺激导致转基因T细胞的凋亡增加。除了T细胞生长和存活失调外，转基因表达还损害正常T细胞群体的发育，这可通过TCRhi CD8单阳性胸腺细胞数量减少来证明。这种缺陷在外周显著放大，并伴有CD4(+) T细胞减少。综上所述，这些体内研究结果表明，NF-κB/Rel信号通路包含对正常T细胞亚群的建立至关重要的补偿性成分。
