Using histone deacetylase inhibitors to enhance Foxp3+ regulatory T-cell function and induce allograft tolerance

Abstract

The histone/protein deacetylase inhibitor (HDACi), trichostatin A (TsA), increases the production and suppressive function of Foxp3+ regulatory T cells (Tregs), at least in part, by promoting the acetylation of Foxp3 protein itself. Acetylation of Foxp3 is required for effective binding of Foxp3 to the promoter of the interleukin-2 (IL-2) gene and the suppression of IL-2 expression. We have sought to identify agents that had similar effects on Tregs, but without the associated toxicity of TsA. This review summarizes the contrasting effects of various HDACis on T reg functions in vitro and in vivo. Agents that block primarily class I HDAC had minimal or no effect on Treg suppression, whereas multiple inhibitors of both class I and class II HDAC enhanced Treg suppression in vitro and in vivo. These data indicate tools for further analysis of Treg functions, and point to a critical role of class II HDAC in the regulation of Tregs. Such knowledge has direct implications for the development of in vivo approaches to treat autoimmune and other inflammatory diseases. © 2009 Australasian Society for Immunology Inc. All rights reserved.