BCL6 in control of the Th2 inflammatory activity of regulatory T cells (168.3)

Abstract

Abstract The transcriptional repressor Bcl6 is a critical arbiter of T helper cell fate, promoting the follicular helper (Tfh) lineage while repressing other T helper cell lineages. Bcl6-deficient (Bcl6-/-) mice develop a spontaneous and severe Th2-type inflammatory disease early in life, thus warranting assessment of the role of Bcl6 in Treg cell function. Bcl6-/- Tregs displayed enhanced suppressor function in vitro and were competent at suppressing Th1-mediated colitogenic inflammation in vivo. In contrast, Bcl6-/- Treg cells were uniquely defective in their ability to control Th2-type airway inflammation, and in fact, actively exacerbated the disease. Bcl6 deficiency promoted the expression of Th2 cytokines by Tregs, in part due to increased transcriptional activity of Gata3, and also due to increased expression of microRNA-21 (miR-21). Ectopic expression of miR-21 in naïve T cells in vitro induced polarization towards Th2, while antagomir-mediated miR-21 repression was able to specifically suppress Th2 differentiation. Our results define novel roles for Bcl6 in regulating Treg gene expression and in dictating the ability of Treg cells to control Th2 inflammation. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program.