Histone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3+ T-Regulatory Cells
Histone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3+ T-Regulatory Cells
复制标题
DOI：
10.1128/mcb.05155-11
复制
发表时间：
2011-05-01
影响因子：
5.3
通讯作者：
Hancock, Wayne W.
中科院分区：
文献类型：
--
作者：
de Zoeten, Edwin F.;Wang, Liqing;Hancock, Wayne W.
Foxp 3（+）T调节细胞（TCRs）是免疫稳态的关键，其数量或功能的减少可引起自身免疫和同种异体移植排斥。Foxp 3（+）TcB表达多种组蛋白/蛋白脱乙酰基酶（HDAC），其调节染色质重塑、基因表达和蛋白质功能。为肿瘤学应用开发的泛HDAC抑制剂增强Treg产生和Treg抑制功能，但鉴于其广泛的作用和各种副作用，其非肿瘤学效用有限。我们使用HDAC 6缺陷小鼠和野生型（WT）小鼠用HDAC 6特异性抑制剂治疗，HDAC 6抑制促进炎症和自身免疫模型中的Treg抑制活性，包括多种形式的实验性结肠炎和完全主要组织相容性复合体（MHC）不相容的心脏同种异体移植排斥反应。HDAC 6靶向的许多有益效果也通过抑制HDAC 6调节蛋白热休克蛋白90（HSP 90）来实现。因此，选择性靶向单一HDAC同种型HDAC 6或其下游靶标HSP 90可以促进自身免疫和移植排斥的Treg依赖性抑制。
Foxp3(+) T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3(+) Tregs express multiple histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression, and protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production and Treg suppression function but have limited nononcologic utility given their broad actions and various side effects. We show, using HDAC6-deficient mice and wild-type (WT) mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein heat shock protein 90 (HSP90). Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection.