JunB and c-Rel cooperatively enhance Foxp3 expression during induced regulatory T cell differentiation.

The function and differentiation of induced regulatory T (iTreg) cells are tightly regulated by various signaling cascade. In this study, we have investigated the role of TCR signaling to induce Foxp3 gene expression in cooperation with TGF-β/IL-2 stimulation. Activation of CD4(+) T cells by TCR signaling or TGF-β/IL-2 alone failed to enhance Foxp3 expression. Only when TCR stimulation is coupled together with TGF-β/IL-2, CD4(+) T cells expressed high levels of Foxp3 by maintaining open chromatin structure around its promoter region. Under this condition, stimulation-dependent recruitment of JunB together with c-Rel enhanced Foxp3 expression. Over expression of JunB and c-Rel significantly enhanced Foxp3 promoter activity while treatment of JunB siRNA or inhibition of TCR signaling by MAPK inhibitors significantly reduced Foxp3 expression. Collectively our results suggest that TCR signaling together with TGF-β/IL-2 stimulation cooperatively enhance Foxp3 gene expression by maintaining accessible chromatin structure and by actively recruiting key transcription factors JunB and c-Rel.