The initial source of IL-4-inducing Th2 development and the mechanism of st
able Th2 commitment remain obscure. We found the reduced level of IL-4 prod
uction in Stat6-deficient T cells to be significantly higher than in Th1 co
ntrols. Using a novel cell surface affinity matrix technique, we found that
IL-4-secreting Stat6-deficient T cells stably expressed GATA-3 and Th2 phe
notype. Introducing GATA-3 into Stat6-deficient T cells completely restored
Th2 development, inducing c-Maf, Th2-specific DNase I hypersensitive sites
in the IL-4 locus, and Th2 cytokine expression. The fact that GATA-3 fully
reconstitutes Th2 development in Stat6-deficient T cells indicates it is a
master switch in Th2 development. Finally, GATA-3 exerts Stat6-independent
autoactivation, creating a feedback pathway stabilizing Th2 commitment.