FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3.

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Regulatory T cells (Tregs) are vital for immune homeostasis and preventing inflammatory diseases.
• Treg function relies on the transcription factor FOXP3 and IL-2 production, regulated by post-translational modifications like acetylation.
• Histone/protein deacetylases (HDACs) play a role in regulating FOXP3 activity.

Purpose of the Study:

• To investigate the role of HDAC3 in the development and function of thymus-derived Tregs and induced Tregs (iTregs).
• To elucidate the molecular mechanisms by which HDAC3 influences Treg biology.

Main Methods:

• Utilized murine models with conditional deletion of Hdac3 in Tregs.
• Examined HDAC3-FOXP3 interaction and its effect on Il2 promoter activity.
• Assessed Treg suppressive function, IL-2 production, and T cell proliferation in vivo.
• Investigated HDAC3's role in iTreg differentiation from conventional T cells.

Main Results:

• HDAC3 physically interacts with FOXP3 and suppresses Il2 promoter activity.
• Conditional deletion of Hdac3 in thymic Tregs restored IL-2 production but abolished their suppressive function.
• HDAC3-deficient mice exhibited early-onset fatal autoimmunity.
• HDAC3-deficient conventional T cells failed to differentiate into iTregs and produced pro-inflammatory cytokines.

Conclusions:

• HDAC3 is essential for the normal development and function of both thymus-derived and induced Tregs.
• HDAC3 acts as a critical regulator of Treg suppressive capacity and immune homeostasis.
• Targeting HDAC3 could have implications for treating autoimmune and inflammatory diseases.