Role Of The Transcriptional Coactivator TAZ In T_H17 And T_reg Cells Differentiation

Autoimmune diseases are types of chronic inflammatory diseases caused by immune response with self-antigens,which usually affect multiple organs and tissues.Such diseases are Crohn’s disease,Rheumatoid arthritis,Sjogren’s syndrome and so on.Recently,a plenty of studies have shown that an imbalance between immunosuppressive regulatory T cells(Treg cells)and the inflammatory TH17 cells leads to develop autoimmune and inflammatory diseases.In this reseach,we found that the expression of TAZ in the naive CD4+ T cells was significantly up-regulated in inflammatory TH17 cells.By using T-cell specific TAZ conditional knockout mice(Tazf1/f1 or TaZf1/f1Lck-Cre mice,termed TAZ cKO mice),we found TAZ was dispensable in T cell activation and proliferation.Further,we found that TAZ deficiency resulted in a decrease of the proportion of IL-17A+ TH17 cells and an increase of the proportion of Foxp3+Treg cells.To further invetigate the mechanism,we found that the polymerized TAZ simultaneously formed complex with RORyt,the core transcription factors of TH17 cells,and Foxp3,key transcription factor of Treg cells with observation of Super-resolution Microscopy and other biochemical experiments.TAZ promotes RORyt AF2 transcriptional activity through its WW domain.On the other hand,TAZ destabilizes Foxp3 protein and inhibits its function by competing with Foxp3 to bind to Tip60,which acetylates Foxp3 by forming complex with p300.Consequently,TAZ promotes the differentiation of TH17 cells and inhibits the production of Treg cells.This study illustrates that TAZ plays a key role in regulating the differentiation of naive CD4+ T cells into TH17 cells and Treg cells.This work provides not only a theoretical basis for the pathogenesis of multiple autoimmune diseases,but a possible molecular marker and therapeutic target for early diagnosis and treatment of chronic inflammatory diseases.