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

作者：Siggs Owen M^*; Yates Adele L; Schlenner Susan; Liston Adrian; Lesage Sylvie; Goodnow Christopher C

来源：Immunology, 2014, 141(4): 587-595.

DOI：10.1111/imm.12220

• genetics
• T cells
• thymic selection

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.

• 出版日期2014-4