Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Str, 44, 39120, Magdeburg, Germany.
Cell Commun Signal. 2013 Jan 14;11:4. doi: 10.1186/1478-811X-11-4.
Signaling through the TCR is crucial for the generation of different cellular responses including proliferation, differentiation, and apoptosis. A growing body of evidence indicates that differences in the magnitude and the duration of the signal are critical determinants in eliciting cellular responses.
Here, we have analyzed signaling dynamics correlating with either unresponsiveness or proliferation induced upon TCR/CD28 ligation in primary human T cells. We used two widely employed methods to stimulate T cells in vitro, antibodies either cross-linked in solution (sAbs) or immobilized on microbeads (iAbs). A comparative analysis of the signaling properties of iAbs and sAbs revealed that, under proliferation-inducing conditions, feedback regulation is markedly different from that leading to an unresponsive state. In fact, upon iAbs stimulation TCR-mediated signaling is prolonged by a positive feedback loop involving Erk, whereas sAbs strongly activate inhibitory molecules that likely terminate signaling. We additionally found that, by enhancing the phosphorylation of Src family kinases under proliferation-inducing conditions, signaling and T-cell activation are terminated.
In summary, our analysis documents TCR signaling kinetics and feedback regulation under conditions of stimulation inducing either unresponsiveness or proliferation.
T 细胞受体（TCR）信号对于产生不同的细胞反应至关重要，包括增殖、分化和凋亡。越来越多的证据表明，信号的幅度和持续时间的差异是引发细胞反应的关键决定因素。
在这里，我们分析了与 TCR/CD28 交联诱导的原发性人 T 细胞无反应或增殖相关的信号动力学。我们使用两种广泛应用的方法在体外刺激 T 细胞，抗体要么在溶液中交联（sAbs），要么固定在微珠上（iAbs）。对 iAbs 和 sAbs 的信号特性进行比较分析表明，在诱导增殖的条件下，反馈调节与导致无反应状态的调节明显不同。事实上，在 iAbs 刺激下，TCR 介导的信号通过涉及 Erk 的正反馈环延长，而 sAbs 则强烈激活可能终止信号的抑制分子。我们还发现，通过在诱导增殖的条件下增强Src 家族激酶的磷酸化，信号和 T 细胞激活被终止。
总之，我们的分析记录了在诱导无反应或增殖的刺激条件下 TCR 信号转导和反馈调节的动力学。
