The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells

Abstract

An imbalance in the lineages of immunosuppressive regulatory T cells (T_reg cells) and the inflammatory T_H17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under T_H17 cell-inducing conditions and was required for T_H17 differentiation and T_H17 cell-mediated inflammatory diseases. TAZ was a critical co-activator of the T_H17-defining transcription factor RORγt. In addition, TAZ attenuated T_reg cell development by decreasing acetylation of the T_reg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under T_reg cell-skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted T_reg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced T_reg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed T_H17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of T_reg cells and T_H17 cells.