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Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development

The catalytic activity of Zap-70 is crucial for T cell 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 Zap-70 catalytic activity in a model of synch...

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Detalles Bibliográficos
Autores principales: Au-Yeung, Byron B., Melichar, Heather J., Ross, Jenny O., Cheng, Debra A., Zikherman, Julie, Shokat, Kevan M., Robey, Ellen A., Weiss, Arthur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095875/
https://www.ncbi.nlm.nih.gov/pubmed/24908390
http://dx.doi.org/10.1038/ni.2918
Descripción
Sumario:The catalytic activity of Zap-70 is crucial for T cell 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 Zap-70 catalytic activity in a model of synchronized thymic selection, we showed that CD4(+)CD8(+) thymocytes integrate multiple, transient, Zap-70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas one hour of signaling was sufficient for negative selection. Titration of Zap-70 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, revealing heterogeneity, even among CD4(+)CD8(+) thymocytes expressing identical TCRs undergoing positive selection.