An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation

Abstract

CD4 T(h) are critical for orchestrating adaptive immune responses. The expression of the transcription factor GATA3 (GATA-binding protein 3) is up-regulated or down-regulated during T(h)2 or T(h)1 cell differentiation, respectively. Furthermore, GATA3 is responsible for induction of T(h)2 differentiation and represses T(h)1 differentiation. In this review, we present an updated view on the molecular mechanisms through which GATA3 regulates T(h)1/T(h)2 differentiation. During T(h)2 cell differentiation, GATA3 directly binds to the T(h)2 cytokine gene locus at several regions and regulates expression. On the other hand, GATA3 inhibits T(h)1 cell differentiation by preventing up-regulation of IL-12 receptor β2 and STAT4 (signal transducer and activator of transcription 4) and neutralization of Runx3 (runt-related transcription factor 3) function through protein-protein interaction. GATA3 may also directly act on the Ifng gene. In summary, GATA3 serves as a transcriptional activator or repressor through direct action on transcriptional machinery and/or affecting chromatin remodeling at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation.

Fig. 1.

Molecular mechanisms of GATA3-mediated regulation of T_h1 and T_h2 cell differentiation. GATA3 expression can be induced by TCR and/or IL-4-mediated signaling. GATA3 induces T_h2 cytokine expression through its direct binding to the Il4/Il13 gene locus at several sites including HSII, HSVa, CGRE as well as RHS5 and RHS6 in the LCR. GATA3 can remodel the chromatin structure of this gene locus such as induction of H3K4 methylation; GATA3 may also directly act on the Il13 gene to induce transcription. GATA3 inhibits T_h1 cell differentiation by at least three distinct mechanisms: inhibition of IL-12Rβ2 and STAT4 expression, suppression of Runx3-mediated IFN-γ production and silencing the Ifng gene by adding H3K27me3 suppressive marks. Our GATA3 ChIPseq data suggest that GATA3 directly binds to Stat4, Il12rb2 and Ifng loci (24).