Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function.

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Foxp3+ T-regulatory (Treg) cells are key targets for transplantation therapies.
• Pharmacologic modulation of Treg function via histone/protein deacetylase inhibitors (HDACi) offers an alternative to cell infusion.
• Selective targeting of HDAC isoforms is necessary due to variable effects of broad-acting HDACi.

Purpose of the Study:

• To investigate the role of HDAC11 in Treg cell function and immune tolerance.
• To evaluate the therapeutic potential of targeting HDAC11 in allograft transplantation models.

Main Methods:

• Utilized mice with constitutive or conditional deletion of HDAC11 in Foxp3+ Treg cells.
• Administered small molecule HDAC11 inhibitors in mouse allograft models.
• Assessed Treg cell suppressive function, Foxp3 and TGF-β expression, and allograft survival.

Main Results:

• Deletion of HDAC11 in Tregs increased their suppressive function and expression of Foxp3 and TGF-β.
• Conditional deletion of HDAC11 in Tregs led to long-term survival of MHC-mismatched cardiac allografts.
• HDAC11 inhibition promoted long-term allograft survival in MHC-disparate strains and prevented transplant arteriosclerosis.

Conclusions:

• HDAC11 plays a critical role in regulating Treg cell function.
• Selective inhibition of HDAC11 represents a promising therapeutic strategy for enhancing transplant tolerance.
• HDAC11 inhibitors may offer novel treatments for transplantation and autoimmune diseases.