Transcriptional Regulation of Gata3 in T Helper Cells by the Integrated Activities of Transcription Factors Downstream of the Interleukin-4 Receptor and T Cell Receptor

Abstract

GATA3 is a critical transcription factor for many developmental processes. During T helper (Th) cell differentiation, GATA3 induces the Th2 and suppresses the Th1 pathway. Stimulation of the T cell receptor (TCR) of naive Th cells in the presence of interleukin 4 (IL-4) induces robust expression of GATA3; however, it is unclear where these signals integrate. Gata3 encodes two transcripts that differ in their alternative, untranslated first exons. We show here the involvement of the TCR-inducible transcription factor NFAT1 in the transcriptional regulation of both Gata3 transcripts following TCR stimulation of naive and differentiated Th2 cells. We also show that IL-4 is important for the initiation and establishment of Gata3 transcription in developing Th2 cells, especially from the distal promoter. The early function of IL-4 can be STAT6 dependent or independent. However, the establishment of the activity of the distal promoter is totally dependent on STAT6, whereas it is likely that the proximal promoter has additional activation mechanisms that are STAT6 independent. Our findings suggest that different combinations of transcription factors downstream of the IL-4 receptor (IL-4R) and TCR finely modulate Gata3 gene expression from its two promoters for optimal Th2 differentiation.