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A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity.

To investigate the role of the kinase Zap70 in T cells, we generated mice expressing a Zap70 mutant whose catalytic activity can be selectively blocked by a small-molecule inhibitor. We found that conventional naive, effector and memory T cells were dependent on the kinase activity of Zap70 for their activation, which demonstrated a nonredundant role for Zap70 in signals induced by the T cell antigen receptor (TCR). In contrast, the catalytic activity of Zap70 was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This Zap70 kinase-independent pathway was sufficient for the suppressive activity of regulatory T cells (T(reg) cells), which was unperturbed by inhibition of the catalytic activity of Zap70. Our results indicate Zap70 is a likely therapeutic target.

Pubmed ID: 21037577

Authors

  • Au-Yeung BB
  • Levin SE
  • Zhang C
  • Hsu LY
  • Cheng DA
  • Killeen N
  • Shokat KM
  • Weiss A

Journal

Nature immunology

Publication Data

December 16, 2010

Associated Grants

  • Agency: NIAMS NIH HHS, Id: F32 AR056174
  • Agency: NIAMS NIH HHS, Id: F32AR056174
  • Agency: NIAMS NIH HHS, Id: RC2 AR058947
  • Agency: NIAMS NIH HHS, Id: RC2AR058947

Mesh Terms

  • Animals
  • Biocatalysis
  • Cell Proliferation
  • Cell Separation
  • Enzyme Inhibitors
  • Flow Cytometry
  • Immunoblotting
  • Immunoprecipitation
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes, Regulatory
  • ZAP-70 Protein-Tyrosine Kinase