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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 (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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Tao R,de Zoeten EF,Ozkaynak E,Chen C,Wang L,Porrett PM,Li B,Turka LA,Olson EN,Greene MI,Wells AD,Hancock WW

doi

10.1038/nm1652

subject

Has Abstract

pub_date

2007-11-01 00:00:00

pages

1299-307

issue

11

eissn

1078-8956

issn

1546-170X

pii

nm1652

journal_volume

13

pub_type

杂志文章

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