Synergistic effect of TGF‐β superfamily members on the induction of Foxp3+ Treg |
| |
Authors: | Ling Lu Jilin Ma Xuehao Wang Julie Wang Feng Zhang Jiangning Yu Ge He Bing Xu David D Brand David A Horwitz Wei Shi Song Guo Zheng |
| |
Institution: | 1. Division of Rheumatology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;2. Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, P. R. China;3. Division of Rheumatology, Immunology and Nephrology, Zhejiang Traditional Chinese Medicine and Western Medicine Hospital, Hangzhou, P. R. China;4. Developmental Biology Program, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA;5. Research Service, Veterans Affairs Medical Center, Memphis, TN, USA |
| |
Abstract: | 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. |
| |
Keywords: | Bone morphogenic proteins Foxp3 Smad TGF‐b Treg |
|
|