Structure and specificity of GATA proteins in Th2 development

Development of Th2 subset of CD4(+) T cells involves the interleukin-1 (IL- 4)- and Stat6-dependent increase in GATA-3 expression during primary activa tion. Recently we reported that the phenotypic stability and factor indepen dence of Th2 cells involves acquisition of an intracellular pathway that ma intains GATA-3 expression. Evidence from retroviral expression studies impl ied that this pathway involved an autoactivation of GATA-3 expression, sinc e Stat6-deficient T cells induced endogenous GATA-3 when infected with GATA -3-expressing retroviruses. That study left unresolved the issue of whether GATA-3 autoactivation was direct or indirect. Several other Th2-specific t ranscription factors have been described, including c-Maf and JunB, We ther efore examined the ability of these other transcription factors to induce G ATA-3 expression and promote Th2 development. Neither c-Maf nor JunB induce d Th2 development in Stat6-deficient CD4(+) T cells, in contrast to GATA-3, Consistent with this indication of a possible direct autoactivation pathwa y, we also observed that heterologous GATA family proteins GATA-1, GATA-2, and GATA-4 were also capable of inducing GATA-3 expression in developing St at6-deficient T cells and promote Th2 development. Mutational analysis reve aled evidence for two distinct mechanisms of GATA-3 action. IL-4 induction by GATA-3 required each of the functional domains to be present, whereas re pression of gamma interferon could occur even when mutants of GATA-3 lackin g the second transactivation domain, TA2, were expressed. The GATA-dependen t induction of the GATA-3 but not the other GATA genes in T cells suggests that T-cell-specific cis elements within the GATA-3 locus likely cooperate with a general GATA recognition motif to allow GATA-3-dependent autoactivat ion.