Zap70 (zeta-chain (TCR) associated protein kinase) is critical for T cell receptor (TCR) signaling. Signal transduction by the TCR plays a critical role in T cell development and in protective and pathological responses mediated by mature T cells.

Tyrosines 315 and 319, which play an important role in Zap70 regulatory autoinhibition, were changed to alanines to create this YYAA mutant strain. ZAP70 protein expression levels are reduced to half in CD4/CD8 double-positive thymocytes and CD8 single positive thymocytes of homozygous mice.

YYAA mice have defects in positive and negative selection of T cells in the thymus. Their T regulatory cell function is greatly impaired. When challenged with zymosan to activate the innate immune system, YYAA mice develop rheumatoid factor autoantibodies, but quite surprisingly failed to develop autoimmune arthritis. The mutations skew the TCR repertoire to a more high-affinity self-reactive population, influencing the propensity to autoimmunity versus autoimmune disease susceptibility.

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Tyrosines 315 and 319, which play an important role in Zap70 regulatory autoinhibition, were changed to alanines to create this hypomorphic YYAA mutant strain. These mice are useful in studies of T cell autoimmune threshold.

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