A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity (49.6)

Abstract

Abstract ZAP-70, a Syk family protein tyrosine kinase, is critical for efficient signaling downstream of the TCR. Our lab and others have previously shown that tyrosine 315 and 319 in the interdomain B positively regulate ZAP-70 function by recruiting Vav1 and Lck, respectively. Surprisingly, in addition to their scaffolding function, we recently discovered that Y315 and Y319 play an important role in the autoinhibition ZAP-70 kinase activity. To address the relative importance of the scaffolding function of these residues versus their autoinhibition function, we generated a knock-in ZAP-70 mutant mouse (YYAA mouse) with Y315 and Y319 both mutated to ananine residues. These YYAA mice showed many similarities to a previously identified ZAP-70 mutant mouse, SKG, which harbors a distinct hypomorphic mutation. Both YYAA and SKG mice have impaired T cell development, hyporesponsiveness to TCR stimulation, and defective positive and negative selection. YYAA mice, like SKG mice, develop rheumatoid factor antibodies, but fail to develop autoimmune arthritis. Analysis of TCR repertoire revealed that qualitative difference in TCR signaling may skew the TCR repertoire in ways that differentially influence propensity to autoimmunity versus autoimmune disease susceptibility.