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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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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
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author Au-Yeung, Byron B.
Melichar, Heather J.
Ross, Jenny O.
Cheng, Debra A.
Zikherman, Julie
Shokat, Kevan M.
Robey, Ellen A.
Weiss, Arthur
author_facet Au-Yeung, Byron B.
Melichar, Heather J.
Ross, Jenny O.
Cheng, Debra A.
Zikherman, Julie
Shokat, Kevan M.
Robey, Ellen A.
Weiss, Arthur
author_sort Au-Yeung, Byron B.
collection PubMed
description 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.
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spelling pubmed-40958752015-01-01 Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development Au-Yeung, Byron B. Melichar, Heather J. Ross, Jenny O. Cheng, Debra A. Zikherman, Julie Shokat, Kevan M. Robey, Ellen A. Weiss, Arthur Nat Immunol Article 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. 2014-06-08 2014-07 /pmc/articles/PMC4095875/ /pubmed/24908390 http://dx.doi.org/10.1038/ni.2918 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Au-Yeung, Byron B.
Melichar, Heather J.
Ross, Jenny O.
Cheng, Debra A.
Zikherman, Julie
Shokat, Kevan M.
Robey, Ellen A.
Weiss, Arthur
Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title_full Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title_fullStr Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title_full_unstemmed Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title_short Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development
title_sort quantitative and temporal requirements revealed for zap-70 catalytic activity during t cell development
topic Article
url 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
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