Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and...

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• Therapeutic inhibition of histone deacetylases (HDACs) such as HDAC6, HDAC9, and sirtuin-1 (Sirt1) enhances regulatory T cell (Treg) function.
• This Treg augmentation is beneficial for patients with autoimmune diseases and organ transplant recipients.
• Distinct mechanisms for individual HDAC inhibition and the efficacy of combined inhibition remain unclear.

Purpose of the Study:

• To compare the suppressive functions of Tregs with varying HDAC deletions or inhibitor treatments.
• To elucidate the distinct mechanisms by which HDAC6, HDAC9, and Sirt1 inhibition impact Treg function.
• To assess the potential of combined HDAC inhibition for therapeutic applications.

Main Methods:

• Comparison of Treg suppressive functions in wild-type mice versus mice with complete or cell-specific HDAC deletions.
• Treatment of Tregs with isoform-selective HDAC inhibitors.
• Analysis of Foxp3 (Forkhead box P3) deacetylation and its effect on transcription factors, including STAT5 (signal transducer and activator of transcription 5).

Main Results:

• HDAC6 inhibition enhanced Treg function, dependent on an intact heat shock response, unlike Sirt1 inhibition.
• HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3 but differentially affected transcription factors controlling Foxp3 expression.
• Loss of HDAC9 specifically stabilized acetylated STAT5, promoting its transcriptional activity.

Conclusions:

• Targeting distinct HDACs enhances Treg function via multiple, additive mechanisms.
• Combined HDAC inhibition holds therapeutic potential for managing autoimmunity and improving organ transplantation outcomes.
• Understanding specific HDAC pathways provides a basis for developing targeted combination therapies.