Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt

The cytokine, transforming growth factor-beta 1 (TGF-beta 1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta 1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-beta 1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gamma t (ROR gamma t), was rapidly induced by TGF-beta 1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that ROR gamma t binding is sufficient for activation of the minimum promoter in the HEK 293T cells. ROR gamma t-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with ROR gamma t through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of ROR gamma t-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.