Abstract
BackgroundSignaling 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.ResultsHere, 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.ConclusionsIn summary, our analysis documents TCR signaling kinetics and feedback regulation under conditions of stimulation inducing either unresponsiveness or proliferation.
Highlights
Signaling through the T cell receptor (TCR) is crucial for the generation of different cellular responses including proliferation, differentiation, and apoptosis
We demonstrate that Antibodies cross-linked in solution (sAbs) activate negative feedback loops that terminate TCR-mediated signaling, whereas stimulation with Immobilized on microbeads (iAbs) results in the establishment of a positive feedback loop involving Erk-mediated phosphorylation of Lck prolonging TCR-mediated signaling
When primary human T cells were treated with iAbs, global tyrosine phosphorylation and the phosphorylation of ZAP70, LAT and PLCγ-1 were weak, but sustained (Figure 1A, B)
Summary
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. Ligation of the T cell receptor (TCR) triggers intracellular signals which may result in the initiation of markedly different cellular programs leading to differentiation, activation, survival, or apoptosis of T cells. How signals are interpreted and translated into specific cellular outcomes has been extensively studied in PC-12 cells [1,2]. In these cells, it appears that differences in the magnitude and the duration of the Erk signal are critical determinants in eliciting the cellular response.
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