Synergistic effect of TGF-β superfamily members on the induction of Foxp3⁺ Treg

TGF-β plays an important role in the induction of Treg and maintenance of immunologic tolerance, but whether other members of TGF-β superfamily act together or independently to achieve this effect is poorly understood. Although others have reported that the bone morphogenetic proteins (BMP) and TGF-β have similar effects on the development of thymocytes and T cells, in this study, we report that members of the BMP family, BMP-2 and -4, are unable to induce non-regulatory T cells to become Foxp3⁺ Treg. Neutralization studies with Noggin have revealed that BMP-2/4 and the BMP receptor signaling pathway is not required for TGF-β to induce naïve CD4⁺CD25^- cells to express Foxp3; however, BMP-2/4 and TGF-β have a synergistic effect on the induction of Foxp3⁺ Treg. BMP-2/4 affects non-Smad signaling molecules including phosphorylated ERK and JNK, which could subsequently promote the differentiation of Foxp3⁺ Treg induced by TGF-β. Data further advocate that TGF-β is a key signaling factor for Foxp3⁺ Treg development. In addition, the synergistic effect of BMP-2/4 and TGF-β indicates that the simultaneous manipulation of TGF-β and BMP signaling might have considerable effects in the clinical setting for the enhancement of Treg purity and yield.