The transcription factor GATA3 is crucial for the differentiation of naive CD4+ T cells into T helper 2 (Th2) cells. Here, we show that deletion of Gata3 allowed the appearance of interferon-γ (IFN-γ)-producing cells in the absence of interleukin-12 (IL-12) and IFN-γ. Such IFN-γ production was transcription factor T-bet independent. Another T-box-containing transcription factor Eomes, but not T-bet, was induced both in GATA3-deficient CD4+ T cells differentiated under Th2 cell conditions and in Th2 cells with enforced Runx3 expression, contributing to IFN-γ production. GATA3 overexpression blocked Runx3-mediated Eomes induction and IFN-γ production, and GATA3 protein physically interacted with Runx3 protein. Furthermore, we found that Runx3 directly bound to multiple regulatory elements of the Ifng gene and that blocking Runx3 function in either Th1 or GATA3-deficient “Th2” cells results in diminished IFN-γ production by these cells. Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-γ production in a STAT4- and T-bet-independent manner.
Highlights
► GATA3 suppresses T-bet-independent IFN-γ production both in vitro and in vivo ► Runx3 binds regulatory elements of Ifng locus to induce expression independently of T-bet ► GATA3 interacts with Runx3 to suppress IFN-γ expression