Article abstract
Nature Medicine 13, 1299 - 1307 (2007)
Published online: 7 October 2007 | doi:10.1038/nm1652
Deacetylase inhibition promotes the generation and function of regulatory T cells
Ran Tao1, Edwin F de Zoeten2,3, Engin Özkaynak1,4, Chunxia Chen1, Liqing Wang1, Paige M Porrett3, Bin Li4, Laurence A Turka3, Eric N Olson5, Mark I Greene4, Andrew D Wells1,4 & Wayne W Hancock1,4
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.
- Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Studies of Pediatric Liver Diseases, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA.
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA.
- Department of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-6082, USA.
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-6082, USA.
- Department of Molecular Biology,University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Correspondence to: Wayne W Hancock1,4 e-mail: whancock@mail.med.upenn.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathwayNature Medicine Letter (01 Jan 2005)
Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosisOncogene Original Article
See all 11 matches for Research