Synergistic effect of TGF-beta superfamily members on the induction of Foxp3+ Treg.
TGF-beta plays an important role in the induction of Treg and maintenance of immunologic tolerance, but whether other members of TGF-beta superfamily act together or independently to achieve this effect is poorly understood. Although others have reported that the bone morphogenetic proteins (BMP) and TGF-beta 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-beta to induce naïve CD4+CD25- cells to express Foxp3; however, BMP-2/4 and TGF-beta 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-beta. Data further advocate that TGF-beta is a key signaling factor for Foxp3+ Treg development. In addition, the synergistic effect of BMP-2/4 and TGF-beta indicates that the simultaneous manipulation of TGF-beta and BMP signaling might have considerable effects in the clinical setting for the enhancement of Treg purity and yield.
Lu
Ling
L
Division of Rheumatology, Department of Medicine, Keck School of Medicine, University of Southern California, and Developmental Biology Program, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA 90033, USA.
Ma
Jilin
J
Wang
Xuehao
X
Wang
Julie
J
Zhang
Feng
F
Yu
Jiangning
J
He
Ge
G
Xu
Bing
B
Brand
David D
DD
Horwitz
David A
DA
Shi
Wei
W
Zheng
Song Guo
SG
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000276:immunology / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology*
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta