TCR activation kinetics and feedback regulation in primary human T cells

Cell Commun Signal. 2013 Jan 14;11:4. doi: 10.1186/1478-811X-11-4.

Abstract

Background: 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.

Results: 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.

Conclusions: In summary, our analysis documents TCR signaling kinetics and feedback regulation under conditions of stimulation inducing either unresponsiveness or proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Cell Proliferation
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological
  • Humans
  • Immobilized Proteins / pharmacology
  • Jurkat Cells
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Phosphorylation
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / metabolism*
  • src-Family Kinases / metabolism

Substances

  • Antibodies
  • Immobilized Proteins
  • Receptors, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases