A genetically selective inhibitor reveals ZAP-70 kinase-dependent checkpoints in T cell development (64.15)
| Autor: | Byron Au-Yeung, Debra Cheng, Chao Zhang, Kevan Shokat, Arthur Weiss |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 186:64.15-64.15 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.186.supp.64.15 |
| Popis: | The tyrosine kinase ZAP-70 is critical for the activation of signal pathways downstream of the TCR. We previously generated a transgenic mouse expressing a ZAP-70 mutant (ZAP-70AS) that is selectively inhibited by a PP1 analog, called 3-methyl benzyl PP1 (3-MB-PP1). This system enables the rapid and specific inhibition of ZAP-70 catalytic activity. We used a combination of ZAP-70 inhibitor treatment with fetal thymic organ culture (FTOC) to determine when ZAP-70 kinase activity is required for proper T cell development. Our results show that treatment of ZAP-70AS FTOC with 3-MB-PP1 impairs development of the CD4 CD8 double-negative 4 (DN4) subset, indicating that ZAP-70 has an important role in pre-TCR signaling and TCR β-chain selection. This block is not complete, allowing generation of double-positive (DP) thymocytes, possibly due to expression of the related kinase Syk. However, ZAP-70 kinase activity is fully required for positive selection, as characterized by DP cell upregulation of surface levels of TCR, CD5 and CD69. Here we show that ZAP-70 kinase activity has both partial and full requisite roles in T cell development. |
| Databáze: | OpenAIRE |
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