Kaufman M, Andris F, Leo O
Centre for Nonlinear Phenomena and Complex Systems, Université Libre de Bruxelles, Belgium.
Int Immunol. 1996 Apr;8(4):613-24. doi: 10.1093/intimm/8.4.613.
Helper T cell signaling is initiated by the aggregation of TCR with the induction of tyrosine kinase activity as one of the earliest consequences. Here, a theoretical model for antigen-induced unresponsiveness is presented that relies on a cascade of tyrosine phosphorylation-dephosphorylation cycles. A mechanism is described for both desensitization in the presence of antigen and persistent lowering of cell responsiveness after stimulus removal. An important component of the model, leading to bistability, is the presence of autophosphorylating protein tyrosine kinases in the early steps of TCR signaling. One of its predictions is that, following stimulation, the net phosphorylative activity of these receptor-associated tyrosine kinases will remain above background level after removal of the antigen. It is proposed that this residual tyrosine kinase activity is linked to a deficient signal transduction capacity of the TCR system that leads to a state of prolonged unresponsiveness. In addition, the present analysis defines the notion of a signaling threshold for hyporesponsiveness induction, associated with a durable switch and amplification of the net tyrosine kinase activity. This approach emphasizes the role of tyrosine kinases in the down-regulation of cellular competence.
辅助性T细胞信号传导始于TCR聚集，并最早诱导酪氨酸激酶活性。在此，我们提出了一种抗原诱导无反应性的理论模型，该模型依赖于一系列酪氨酸磷酸化-去磷酸化循环。描述了一种机制，用于解释在存在抗原时的脱敏作用以及刺激去除后细胞反应性的持续降低。该模型的一个重要组成部分，导致双稳态的是TCR信号传导早期步骤中存在自磷酸化蛋白酪氨酸激酶。其预测之一是，在刺激后，去除抗原后这些受体相关酪氨酸激酶的净磷酸化活性将保持在背景水平之上。有人提出，这种残余的酪氨酸激酶活性与TCR系统信号转导能力不足有关，导致长期无反应状态。此外，本分析定义了低反应性诱导信号阈值的概念，与净酪氨酸激酶活性的持久转换和放大相关。这种方法强调了酪氨酸激酶在细胞能力下调中的作用。
