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

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

Author information

1
1] Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA. [2] Rosalind Russell-Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [4] Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA. [5].
2
1] Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. [2] [3].
3
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
4
1] Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA. [2] Rosalind Russell-Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [4] Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
5
1] Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA. [2] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.

Erratum in

  • Nat Immunol. 2015 Feb;16(2):214.

Abstract

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.

PMID:
24908390
PMCID:
PMC4095875
DOI:
10.1038/ni.2918
[Indexed for MEDLINE]
Free PMC Article

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