Using histone deacetylase inhibitors to enhance Foxp3(+) regulatory T-cell function and induce allograft tolerance.
The histone/protein deacetylase inhibitor (HDACi), trichostatin A (TsA), increases the production and suppressive function of Foxp3(+) regulatory T cells (T(regs)), 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 T(regs), 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 T(reg) suppression, whereas multiple inhibitors of both class I and class II HDAC enhanced T(reg) suppression in vitro and in vivo. These data indicate tools for further analysis of T(reg) functions, and point to a critical role of class II HDAC in the regulation of T(regs). Such knowledge has direct implications for the development of in vivo approaches to treat autoimmune and other inflammatory diseases.
Wang
Liqing
L
Department of Pathology and Laboratory Medicine, Stokes Research Institute and Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104-4318, USA.
Tao
Ran
R
Hancock
Wayne W
WW
D000107:Acetylation; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D044127:Epigenesis, Genetic / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007108:Immune Tolerance / Q000187:drug effects*; D007376:Interleukin-2 / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects*
D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007376:Interleukin-2; C012589:trichostatin A