The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway

The transcriptional repressor Bcl6 is a critical regulator of T helper cell fate, and inhibits Th2-type inflammation. We have found that microRNA-21 (miR-21) is a novel target gene for Bcl6 in Treg cells. Bcl6 represses and Stat3 activates miR-21 transcription through a Stat3 binding element in the promoter, indicating opposing regulation of miR-21 by the two transcription factors via the same DNA site. Ectopic expression of miR-21 promoted Th2 differentiation in non-polarized T cells. The pro-Th2 activity of miR-21 was associated with increased Gata3 expression and decreased expression of the miR-21 target gene Sprouty1. Increased miR-21 promoted Th2 and Treg gene expression in wild-type Tregs. MiR-21 could thus help promote the Th2 bias of Bcl6-deficient conventional T cells and Treg cells. MiR21 expression is increased in Th2-type inflammation, and our results define miR-21 as a critical target of Bcl6, thus providing a new link between Bcl6 and Th2 inflammation. Finally, our results reveal a novel T cell autonomous role for miR-21 in promoting Th2 differentiation.

► MicroRNA-21 (miR-21) is a novel target gene for Bcl6 in Treg cells. ► Bcl6 represses and Stat3 activates miR-21 transcription through a Stat3 binding element in the promoter, indicating opposing regulation of miR-21 by Bcl6 and Stat3. ► Expression of miR-21 promoted Th2 differentiation in non-polarized T cells by a novel T cell intrinsic pathway. ► The pro-Th2 activity of miR-21 was associated with increased Gata3 expression and decreased expression of the miR-21 target gene Sprouty1.