REV-ERBα Regulates T_H17 Cell Development and Autoimmunity

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• T helper 17 (T_H17) cells are crucial for immunity but implicated in autoimmune diseases.
• RORγt is the key transcription factor for T_H17 cell development.
• Mechanisms that negatively regulate T_H17 cells and autoimmunity are not fully understood.

Purpose of the Study:

• To investigate the role of the transcriptional repressor REV-ERBα in T_H17 cell development and function.
• To explore REV-ERBα as a potential therapeutic target for T_H17-mediated autoimmune conditions.

Main Methods:

• Analysis of REV-ERBα expression in T_H17 cells.
• Investigating the interaction between REV-ERBα and RORγt at shared DNA consensus sequences.
• Assessing the impact of REV-ERBα deletion on T_H17 cell responses in vivo.
• Evaluating the therapeutic potential of REV-ERB-specific synthetic ligands in experimental autoimmune encephalomyelitis (EAE) and colitis models.

Main Results:

• REV-ERBα is exclusively expressed in T_H17 cells and negatively regulates their development by repressing RORγt-dependent genes, including Il17a.
• Deletion of REV-ERBα enhanced T_H17-mediated inflammation, worsening EAE and colitis.
• REV-ERB-specific ligands suppressed T_H17 cell development and ameliorated disease in EAE and colitis models without affecting thymic cellularity.

Conclusions:

• REV-ERBα acts as a critical negative regulator of pro-inflammatory T_H17 responses in vivo.
• REV-ERBs represent promising therapeutic targets for treating T_H17-driven autoimmune diseases.