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

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.

SUBMITTER: Au-Yeung BB

PROVIDER: S-EPMC4095875 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Au-Yeung Byron B BB Melichar Heather J HJ Ross Jenny O JO Cheng Debra A DA Zikherman Julie J Shokat Kevan M KM Robey Ellen A EA Weiss Arthur A

Nature immunology 20140608 7

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 ...[more]

PMID: 24908390

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