A novel Zap70 mutation with reduced protein stability demonstrates the rate‐limiting threshold for Zap70 in T‐cell receptor signalling. Issue 3 (March 2014)

• Record Type: Journal Article
• Authors: Cauwe, Bénédicte; Tian, Lei; Franckaert, Dean; Pierson, Wim; Staats, Kim A.; Schlenner, Susan M.; Liston, Adrian
• Is Part Of: Immunology. Volume 141:Issue 3(2014:Mar.)
• Page Start: 377
• Page End: 387
• Publication Date: 2014-03
• Subjects: Immunology -- Periodicals
• DOI: 10.1111/imm.12199
• Languages: English
• ISSNs: 0019-2805

Abstract

<abstract abstract-type="main" id="imm12199-abs-0001"> <title>Summary</title> <p>Loss of <italic>ζ</italic>‐associated protein 70 (Zap70) results in severe immunodeficiency in humans and mice because of the critical role of Zap70 in T‐cell receptor (TCR) signalling. Here we describe a novel mouse strain generated by <italic>N</italic>‐ethyl‐<italic>N</italic>‐nitrosourea mutagenesis, with the <italic>reduced protein stability</italic> (<italic>rps</italic>) mutation in Zap70. The A243V <italic>rps</italic> mutation resulted in decreased Zap70 protein and a reduced duration of TCR‐induced calcium responses, equivalent to that induced by a 50% decrease in catalytically active Zap70. The reduction of signalling through Zap70 was insufficient to substantially perturb thymic differentiation of conventional CD4 and CD8 T cells, although Foxp3⁺ regulatory T cells demonstrated altered thymic production and peripheral homeostasis. Despite the mild phenotype, the Zap70^A243V variant lies just above the functional threshold for TCR signalling competence, as T cells relying on only a single copy of the <italic>Zap70</italic>^{<italic>rps</italic>} allele for TCR signalling demonstrated no intracellular calcium response to TCR stimulation. This addition to the Zap70 allelic series indicates that a rate‐limiting threshold for Zap70 protein levels exists at which signalling capacity switches from nearly intact to effectively null.</p> </abstract>