title: TCR activation kinetics and feedback regulation in primary human T cells.
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.
authors: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Str, 44, 39120, Magdeburg, Germany. luca.simeoni@med.ovgu.de.
authors: Mateusz
authors: M
authors: Poltorak
authors: Boerge
authors: B
authors: Arndt
authors: Bhavani S
authors: BS
authors: Kowtharapu
authors: Amarendra V
authors: AV
authors: Reddycherla
authors: Vanessa
authors: V
authors: Witte
authors: Jonathan A
authors: JA
authors: Lindquist
authors: Burkhart
authors: B
authors: Schraven
authors: Luca
authors: L
authors: Simeoni
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D055767:Immobilized Proteins / Q000494:pharmacology; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D055767:Immobilized Proteins; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases