A mechanism underlying STAT4-mediated up-regulation of IFN- induction inTCR-triggered T cells

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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.

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