Interleukin-4 Receptor Alpha Chain ITIM Motif Mutant Mice Potentiate Stat6 Activation and IgE Production

Abstract

RATIONALE: Signaling via the IL-4 receptor alpha chain (IL-4Rα) plays a critical role in the evolution of Th2 responses and the pathology of allergic diseases such as asthma. The IL-4Rα is endowed with an immunoreceptor tyrosine-based inhibitory motif (ITIM) at the fifth tyrosine residue in the cytoplasmic domain of IL-4Rα (Y709). This motif binds a number of SH2-containing phosphatases, including SHP-1, SHP-2, and SHIP. Its role in vivo remains unclear. METHODS: The in vivo function of this ITIM motif in IL-4R signaling was analyzed in mutant mice in which the Y709 residue was mutated into phenylalanine (Y709F) by knockin mutagenesis. RESULTS: B cells from the Y709F mutation demonstrated enhanced Stat6 but not Jak1 phosphorylation following IL-4 stimulation. In vivo, the Y709F mutant mice exhibited increased baseline levels of IgE in the serum and augmented total and antigen-specific IgE responses following immunization. T lymphocytes from this mutation also exhibit significantly increased production of IL-4 in a Th2 polarized milieu. CONCLUSIONS: These results point to a negative regulatory role for the Y709 ITIM motif in signaling via IL-4Rα in vivo. Mutations or polymorphisms that affect ITIM function may play an important role in disease pathogenesis of allergic inflammation such as asthma.