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Deacetylase inhibition promotes the generation and function of regulatory T cells

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 Treg-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, Treg-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.

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Figure 1: HDACi therapy increases the numbers of Foxp3+ CD4+ CD25+ Treg cells in vivo.
Figure 2: HDACi therapy enhances Treg gene expression and suppressive function.
Figure 3: HDAC expression in Treg cells.
Figure 4: Foxp3 acetylation and Treg function.
Figure 5: HDACi therapy enhances Treg function in vivo.
Figure 6: HDACi and effector–T cell responses.

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Acknowledgements

This work was supported by a US National Institutes of Health grant to W.W.H. (R01 AI 54720).

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Contributions

R.T. performed most of the transplant and in vitro studies, E.F.D.Z. performed colitis studies, E.O. performed Foxp3 mutagenesis, C.C. and A.D.W. performed ChIP studies, L.W. performed additional transplant and in vitro experiments, P.M.P. and L.A.T. performed peripheral conversion studies with Fox-GFP transgenic mice, B.L., M.I.G. and E.N.O. were instrumental in early stages of the project, and W.W.H. conceived, designed and directed the study and wrote the manuscript.

Corresponding author

Correspondence to Wayne W Hancock.

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Tao, R., de Zoeten, E., Özkaynak, E. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13, 1299–1307 (2007). https://doi.org/10.1038/nm1652

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