REV-ERB regulates RORγt+ regulatory T cell specification and function through the Bhlhe40-c-Maf axis.

Foxp3+ regulatory T (Treg) cells co-expressing RORγt adopt specialized functions to restrain intestinal inflammation. However, despite extensive characterization, the factors governing RORγt+Foxp3+ Treg specialization remain unclear. Here, we report that transcriptional repressor REV-ERB is critical for the differentiation and function of colonic RORγt+Foxp3+ Treg cells. REV-ERB deficiency exacerbates both TNBS- and oxazolone-induced intestinal inflammation. Mechanistically, REV-ERB promotes RORγt expression through suppressing the expression of transcriptional repressor Bhlhe40, which in turn inhibits c-Maf, a key factor promoting colonic RORγt+Foxp3+ Treg differentiation and function. Moreover, this Bhlhe40-c-Maf axis downstream of REV-ERB also regulates the expression of core colonic Treg signature genes including IL-10 and CTLA-4, while REV-ERB additionally safeguards RORγt+Foxp3+ Treg functional stability by directly suppressing proinflammatory cytokine IL-17A production. Collectively, the present study identifies that REV-ERB along with the downstream Bhlhe40-c-Maf axis jointly controls the RORγt+Foxp3+ Treg differentiation and suppressive function, suggesting that modulating their activities may strengthen RORγt+Foxp3+ Treg function to ameliorate inflammatory bowel diseases.