Blimp-1 Functions as a Molecular Switch to Prevent Inflammatory Activity in Foxp3+ROR?t+ Regulatory T Cells.

ABSTRACT: Foxp3+ regulatory T cells (Treg) are essential modulators of immune responses, but the molecular mechanisms underlying their function are not fully understood. Here we show that the transcription factor Blimp-1 is a crucial regulator of the Foxp3+ROR?t+ Treg subset. The intrinsic expression of Blimp-1 in these cells is required to prevent production of Th17-associated cytokines. Direct binding of Blimp-1 to the Il17 locus in Treg is associated with inhibitory histone modifications but unaltered binding of ROR?t. In the absence of Blimp-1, the Il17 locus is activated, with increased occupancy of the co-activator p300 and abundant binding of the transcriptional regulator IRF4, which is required, along with ROR?t, for IL-17 expression in the absence of Blimp-1. We also show that despite their sustained expression of Foxp3, Blimp-1-/- ROR?t+IL-17-producing Treg lose suppressor function and can promote intestinal inflammation, indicating that repression of Th17-associated cytokines by Blimp-1 is a crucial requirement for ROR?t+ Treg function.

SUBMITTER: Ogawa C 

PROVIDER: S-EPMC6237548 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature