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

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• Foxp3+ regulatory T (Treg) cells expressing RORγt are vital for controlling intestinal inflammation.
• The specific factors driving RORγt+Foxp3+ Treg specialization are not fully understood.

Purpose of the Study:

• To investigate the role of the transcriptional repressor REV-ERB in the differentiation and function of colonic RORγt+Foxp3+ Treg cells.
• To elucidate the molecular mechanisms by which REV-ERB influences Treg specialization and intestinal inflammation.

Main Methods:

• Utilized mouse models of chemically induced colitis (TNBS and oxazolone).
• Analyzed gene expression and protein levels related to Treg differentiation and function.
• Investigated the regulatory axis involving REV-ERB, Bhlhe40, and c-Maf.

Main Results:

• REV-ERB deficiency significantly worsened intestinal inflammation in mouse models.
• REV-ERB was found to suppress Bhlhe40, thereby promoting RORγt expression via c-Maf.
• The REV-ERB/Bhlhe40-c-Maf pathway regulates key Treg genes (IL-10, CTLA-4) and suppresses IL-17A production.

Conclusions:

• REV-ERB is essential for the differentiation and function of colonic RORγt+Foxp3+ Treg cells.
• The Bhlhe40-c-Maf axis, downstream of REV-ERB, plays a critical role in Treg specialization.
• Targeting REV-ERB or its downstream pathways may offer a therapeutic strategy for inflammatory bowel diseases.