Title: A ZAP-70 kinase domain variant prevents thymocyte positive selection despite signalling CD69 induction
Authors: Siggs, Owen M ×
Yates, Adèle L
Schlenner, Susan
Liston, Adrian
Lesage, Sylvie
Goodnow, Christopher C #
Issue Date: Apr-2014
Publisher: Blackwell Scientific Publications
Series Title: Immunology vol:141 issue:4 pages:587-95
Article number: 10.1111/imm.12220
Abstract: Quantitative reductions in TCR signalling are associated with severe immunodeficiency, yet in certain cases can lead to autoimmunity. Mutation of the tyrosine kinase ZAP-70 can cause either of these outcomes, yet the limits of its signal transducing capacity are not well defined. To investigate these limits we have made use of mrtless: a chemically-induced mutation of Zap70 associated with T cell-deficiency. Unlike cells devoid of ZAP-70, mrtless thymocytes showed partial induction of CD5 and CD69, and were sensitive to T cell receptor stimulation with a dose response shifted approximately 10-fold. However, essentially no T cells were able to compensate for the mrtless mutation and mature beyond the CD4(+) CD8(+) stage. This outcome contrasts with a ZAP-70 Src homology 2 (SH2)-domain mutant strain, where high affinity self-reactive TCRs are positively selected rather than deleted. We discuss these data with respect to current models of TCR signalling in thymocyte selection. This article is protected by copyright. All rights reserved.
ISSN: 0019-2805
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Genetics of Autoimmunity (VIB-KU Leuven Center for Brain & Disease Research)
× corresponding author
# (joint) last author

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