REV-ERB regulates RORgammat+ regulatory T cell specification and function through the Bhlhe40-c-Maf axis #MMPMID41359309
Hu X; Liu Z; Li Y; You Y; Yue K; Liang Y; Loo CS; Yu J; Leblanc M; Wang D; Li H; Zheng Y
J Exp Med 2026[Feb]; 223 (2): ? PMID41359309show ga
Foxp3+ regulatory T (Treg) cells co-expressing RORgammat adopt specialized functions to restrain intestinal inflammation. However, despite extensive characterization, the factors governing RORgammat+Foxp3+ Treg specialization remain unclear. Here, we report that transcriptional repressor REV-ERB is critical for the differentiation and function of colonic RORgammat+Foxp3+ Treg cells. REV-ERB deficiency exacerbates both TNBS- and oxazolone-induced intestinal inflammation. Mechanistically, REV-ERB promotes RORgammat expression through suppressing the expression of transcriptional repressor Bhlhe40, which in turn inhibits c-Maf, a key factor promoting colonic RORgammat+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 RORgammat+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 RORgammat+Foxp3+ Treg differentiation and suppressive function, suggesting that modulating their activities may strengthen RORgammat+Foxp3+ Treg function to ameliorate inflammatory bowel diseases.
J+Exp+Med 2026 ; 223 (2): ?
