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A novel Zap70 mutation with reduced protein stability demonstrates the rate‐limiting threshold for Zap70 in T‐cell receptor signalling
Author(s) -
Cauwe Bénédicte,
Tian Lei,
Franckaert Dean,
Pierson Wim,
Staats Kim A.,
Schlenner Susan M.,
Liston Adrian
Publication year - 2014
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12199
Subject(s) - zap70 , biology , t cell receptor , microbiology and biotechnology , t cell , immunology , immune system
Summary Loss of ζ ‐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 N ‐ethyl‐ N ‐nitrosourea mutagenesis, with the reduced protein stability ( rps ) mutation in Zap70 . The A243V rps 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 CD 4 and CD 8 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 Zap70 rps 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.