Cargando…

Releasing Ski-Smad4 mediated suppression is essential to license Th17 differentiation

Th17 cells are critically involved in host defense, inflammation, and autoimmunity(1–5). TGF-β is instrumental in Th17 differentiation by cooperating with IL-6(6,7). Yet, the mechanism of how TGF-β enables Th17 differentiation remains elusive. Here we reveal that TGF-β licenses Th17 differentiation...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Song, Takaku, Motoki, Zou, Liyun, Gu, Ai-di, Chou, Wei-chun, Zhang, Ge, Wu, Bing, Kong, Qing, Thomas, Seddon Y., Serody, Jonathan S., Chen, Xian, Xu, Xiaojiang, Wade, Paul A., Cook, Donald N., Ting, Jenny P., Wan, Yisong Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743442/
https://www.ncbi.nlm.nih.gov/pubmed/29072299
http://dx.doi.org/10.1038/nature24283
Descripción
Sumario:Th17 cells are critically involved in host defense, inflammation, and autoimmunity(1–5). TGF-β is instrumental in Th17 differentiation by cooperating with IL-6(6,7). Yet, the mechanism of how TGF-β enables Th17 differentiation remains elusive. Here we reveal that TGF-β licenses Th17 differentiation by releasing Ski-Smad4-complex suppressed RORγt expression. We found serendipitously that, unlike wild-type T cells, Smad4-deficient T cells differentiated into Th17 cells in the absence of TGF-β signaling in a RORγt-dependent manner. Ectopic Smad4 expression suppressed the RORγt expression and Th17 differentiation of Smad4-deficient T cells. Unexpectedly however, TGF-β neutralized Smad4 mediated suppression without affecting Smad4 binding to Rorc locus. Proteomic analysis revealed that Smad4 interacted with Ski, a transcriptional repressor degraded upon TGF-β stimulation. Ski controlled the histone acetylation/de-acetylation of Rorc locus and Th17 differentiation via Smad4 because ectopic Ski expression inhibited H3K9Ac of Rorc locus, Rorc expression and Th17 differentiation in a Smad4-dependent manner. Therefore, TGF-β-induced disruption of Ski releases Ski-Smad4 complex imposed suppression of RORγt to license Th17 differentiation. This study reveals a critical mechanism by which TGF-β controls Th17 differentiation and uncovers Ski-Smad4 axis as a potential therapeutic target for treating Th17 related diseases.