Deacetylase inhibition promotes the generation and function of regulatory T cells

Nat Med. 2007 Nov;13(11):1299-307. doi: 10.1038/nm1652. Epub 2007 Oct 7.


Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (T(reg) cells). Although T(reg) cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal T(reg) function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced T(reg)-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through T(reg)-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, T(reg)-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3(+) T(reg) cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Forkhead Transcription Factors / biosynthesis
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / biosynthesis
  • Histone Deacetylases / genetics
  • Hydroxamic Acids / pharmacology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Congenic
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / enzymology*
  • T-Lymphocytes, Regulatory / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • trichostatin A
  • Histone Deacetylases