A mechanism underlying STAT4-mediated up-regulation of IFN-γ induction in TCR-triggered T cells

Abstract

IL-12 promotes Th1 development/IFN-γ expression by activating STAT4. However, it is still unclear how STAT4 elicits IFN-γ promoter activation. Here, we investigated the mechanism by which IL-12-activated STAT4 functions for IFN-γ induction in TCR-triggered T cells. TCR stimulation induced high levels of IFN-γ production depending on co-stimulation with IL-12. IL-12 stimulation greatly enhanced the promoter-binding activity of c-Jun/AP-1, a critical transcription factor for IFN-γ gene expression in wild-type T cells, but not in STAT4-deficient (STAT4-/-) T cells. Comparable amounts of c-Jun were induced by TCR stimulation in both wild-type and STAT4-/- T cells irrespective of IL-12 co-stimulation. However, c-Jun bound to STAT4 in IL-12-co-stimulated wild-type T cells. c-Jun forming a complex with STAT4 efficiently interacted with the AP-1-related sequence of the IFN-γ promoter. Such an enhanced c-Jun binding did not occur in STAT4-/- T cells. These results show that STAT4 contributes to enhancing IFN-γ expression by up-regulating the binding of TCR signal-induced AP-1 to the relevant promoter sequence.