title: A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction.
abstract: 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.
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Siggs
authors.forename: Adèle L
authors.initials: AL
authors.lastname: Yates
authors.forename: Susan
authors.initials: S
authors.lastname: Schlenner
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D018956:CD5 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000378:metabolism; D005838:Genotype; D037181:Lectins, C-Type / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010641:Phenotype; D015398:Signal Transduction; D060168:Thymocytes / Q000201:enzymology* / Q000276:immunology; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018956:CD5 Antigens; D061025:Costimulatory and Inhibitory T-Cell Receptors; D037181:Lectins, C-Type; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C526836:Cd5 protein, mouse; C497262:Zap70 protein, mouse
keywords: T cells; genetics; thymic selection