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However, despite extensive characterization, the factors governing ROR\u03b3t+Foxp3+ Treg specialization remain unclear. Here, we report that transcriptional repressor REV-ERB is critical for the differentiation and function of colonic ROR\u03b3t+Foxp3+ Treg cells. REV-ERB deficiency exacerbates both TNBS- and oxazolone-induced intestinal inflammation. Mechanistically, REV-ERB promotes ROR\u03b3t expression through suppressing the expression of transcriptional repressor Bhlhe40, which in turn inhibits c-Maf, a key factor promoting colonic ROR\u03b3t+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 ROR\u03b3t+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 ROR\u03b3t+Foxp3+ Treg differentiation and suppressive function, suggesting that modulating their activities may strengthen ROR\u03b3t+Foxp3+ Treg function to ameliorate inflammatory bowel diseases.<\/jats:p>","DOI":"10.1084\/jem.20241463","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T06:21:13Z","timestamp":1761373273000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["REV-ERB regulates ROR\u03b3t+ regulatory T cell specification and function through the Bhlhe40-c-Maf 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