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

Immunology. 2014 Apr;141(4):587-95. doi: 10.1111/imm.12220.


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.

Keywords: T cells; genetics; thymic selection.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • CD5 Antigens / metabolism
  • Cells, Cultured
  • Costimulatory and Inhibitory T-Cell Receptors / metabolism
  • Genotype
  • Lectins, C-Type / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutation, Missense*
  • Phenotype
  • Signal Transduction*
  • Thymocytes / enzymology*
  • Thymocytes / immunology
  • Up-Regulation
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD5 Antigens
  • CD69 antigen
  • Cd5 protein, mouse
  • Costimulatory and Inhibitory T-Cell Receptors
  • Lectins, C-Type
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse