Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development

Nat Immunol. 2014 Jul;15(7):687-94. doi: 10.1038/ni.2918. Epub 2014 Jun 8.


The catalytic activity of Zap70 is crucial for T cell antigen receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap70 catalytic activity in a model of synchronized thymic selection, we showed that CD4(+)CD8(+) thymocytes integrate multiple, transient, Zap70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas 1 h of signaling was sufficient for negative selection. Titration of Zap70 activity resulted in graded reductions in positive and negative selection but did not decrease the cumulative TCR signals integrated by positively selected OT-I cells, which revealed heterogeneity, even among CD4(+)CD8(+) thymocytes expressing identical TCRs undergoing positive selection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Catalysis
  • Cell Differentiation
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Protein-Tyrosine Kinases / physiology
  • Receptors, Antigen, T-Cell / physiology
  • Signal Transduction
  • Syk Kinase
  • T-Lymphocytes / physiology*
  • ZAP-70 Protein-Tyrosine Kinase / physiology*


  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, T-Cell
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • Calcium