A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction

Owen M. Siggs, Adèle L. Yates, Susan Schlenner, Adrian Liston, Sylvie Lesage, Christopher C. Goodnow

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Summary: Quantitative reductions in T-cell receptor (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 TCR 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 domain mutant strain, where high-affinity self-reactive TCR are positively selected rather than deleted. We discuss these data with respect to current models of TCR signalling in thymocyte selection.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalImmunology
Volume141
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • Genetics
  • T cells
  • Thymic selection

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