Tao Ran, de Zoeten Edwin F, Ozkaynak Engin, Chen Chunxia, Wang Liqing, Porrett Paige M, Li Bin, Turka Laurence A, Olson Eric N, Greene Mark I, Wells Andrew D, Hancock Wayne W
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.
Nat Med. 2007 Nov;13(11):1299-307. doi: 10.1038/nm1652. Epub 2007 Oct 7.
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.
组蛋白/蛋白质去乙酰化酶（HDACs）可调节染色质重塑和基因表达，以及50多种转录因子和非组蛋白的功能。我们发现，体内给予HDAC抑制剂（HDACi）可增加Foxp3基因表达，以及调节性T细胞（Treg细胞）的产生和抑制功能。尽管Treg细胞表达多种HDACs，但HDAC9在调节Foxp3依赖性抑制中尤为重要。最佳的Treg功能需要Foxp3叉头结构域中多个赖氨酸的乙酰化，而Foxp3乙酰化增强了Foxp3与Il2启动子的结合，并抑制内源性IL-2的产生。体内HDACi治疗增强了Treg介导的稳态增殖抑制作用，通过Treg依赖性效应减轻了炎症性肠病，并且与短疗程低剂量雷帕霉素联合使用时，可诱导永久性的、Treg依赖性的心脏和胰岛同种异体移植存活以及供体特异性同种异体移植耐受。我们的数据表明，使用HDACi可实现对Foxp3(+) Treg细胞数量和抑制功能的有益药理学增强。
