RNA binding protein DDX5 restricts RORγt(+) T(reg) suppressor function to promote intestine inflammation

Retinoid-related orphan receptor (RAR) gamma (RORγt)–expressing regulatory T cells (RORγt(+) T(regs)) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt(+) T(regs). This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt(+) T(regs). T cell–specific Ddx5 knockout (DDX5(ΔT)) mice have augmented RORγt(+) T(reg) suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5(ΔT) mice. The DDX5–HIF1α–IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.