Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
Mol Immunol. 2011 Jul;48(12-13):1369-76. doi: 10.1016/j.molimm.2011.02.015. Epub 2011 Apr 8.
Induction of the TCR signaling pathway terminates the expression of RAG genes, and a link between this pathway and their transcriptional control is evident from the recent demonstration of their re-expression if the TCR is subsequently lost or down-regulated. Since unstimulated T cells display a steady-state level of "tonic" TCR signaling, i.e. in the absence of any antigenic stimulus, it was uncertain whether this control was exerted through ligand-dependent or ligand-independent TCR signaling. Here we demonstrate for the first time that exogenous TCR α and β chains transferred into the human immature RAG(+) T cell line Sup-T1 by lentiviral transduction inhibit RAG expression through tonic signaling, and that this inhibition could itself be reverted by pharmacological tonic pathway inhibitors. We also suggest that mature T cells already expressing an endogenous TCR on their surface maintain some levels of plasticity at the RAG locus when their basal TCR signaling is interfered with. Lastly, we show that the TCR constructs employed in TCR gene therapy do not possess the same basal signaling transduction capability, a feature that may have therapeutic implications.
T 细胞受体信号通路的诱导终止了 RAG 基因的表达，而最近的研究表明，如果 T 细胞受体随后丢失或下调，它们的转录控制与该通路之间存在联系。由于未受刺激的 T 细胞显示出稳定的“基础”T 细胞受体信号，即在没有任何抗原刺激的情况下，不确定这种控制是通过配体依赖性还是配体非依赖性 T 细胞受体信号传导来发挥作用。在这里，我们首次证明，通过慢病毒转导转入人类未成熟 RAG(+)T 细胞系 Sup-T1 的外源性 TCRα和 TCRβ链通过基础信号抑制 RAG 表达，并且这种抑制本身可以通过药理学基础途径抑制剂逆转。我们还表明，当它们的基础 TCR 信号受到干扰时，表面已经表达内源性 TCR 的成熟 T 细胞在 RAG 基因座上仍保持一定程度的可塑性。最后，我们表明，TCR 基因治疗中使用的 TCR 构建体不具有相同的基础信号转导能力，这一特征可能具有治疗意义。
