Deacetylase inhibition promotes the generation and function of regulatory T cells.
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.
Tao
Ran
R
Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Studies of Pediatric Liver Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA.
de Zoeten
Edwin F
EF
Ozkaynak
Engin
E
Chen
Chunxia
C
Wang
Liqing
L
Porrett
Paige M
PM
Li
Bin
B
Turka
Laurence A
LA
Olson
Eric N
EN
Greene
Mark I
MI
Wells
Andrew D
AD
Hancock
Wayne W
WW
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D006655:Histone Deacetylases