Deacetylase inhibition promotes the generation and function of regulatory T cells

Ran Tao, Edwin F. De Zoeten, Engin Özkaynak, Chunxia Chen, Liqing Wang, Paige M. Porrett, Bin Li, Laurence A. Turka, Eric N. Olson, Mark I. Greene, Andrew D. Wells, Wayne W. Hancock

Research output: Contribution to journalArticle

601 Scopus citations

Abstract

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 (Treg cells). Although Treg cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal Treg 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 Treg-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+ Treg cells.

Original languageEnglish (US)
Pages (from-to)1299-1307
Number of pages9
JournalNature medicine
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Tao, R., De Zoeten, E. F., Özkaynak, E., Chen, C., Wang, L., Porrett, P. M., Li, B., Turka, L. A., Olson, E. N., Greene, M. I., Wells, A. D., & Hancock, W. W. (2007). Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature medicine, 13(11), 1299-1307. https://doi.org/10.1038/nm1652