Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Sci Signal. 2012 Jul 31;5(235):pe32. doi: 10.1126/scisignal.2003364.
To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (T(regs)) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of T(regs). Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. T(reg) suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to T(reg) function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance T(reg) stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCF(Skp2). Together, these findings reveal new signaling targets for enhancing T(reg) or effector T cell function that may be helpful in designing future therapies, either to increase T(reg) suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells.
为了应对感染，静息或幼稚 T 细胞必须经历激活、克隆扩增，并分化为效应 T 细胞的专门功能亚群。然而，为了防止过度或自毁性的免疫反应，调节性 T 细胞（Tregs）在抑制效应细胞（包括效应 T 细胞）的激活和功能方面发挥着重要作用。转录因子叉头框 P3（Foxp3）调节参与 Tregs 发育和功能的基因的表达。Foxp3 与其他转录因子相互作用，并与表观遗传元件（如组蛋白去乙酰化酶（HDACs）和组蛋白乙酰转移酶）相互作用。Treg 的抑制功能可通过暴露于 HDAC 抑制剂来增强。然而，不同的 HDAC 家族成员对 Treg 功能的个体贡献及其各自的作用机制仍不清楚。一项研究表明，HDAC6、HDAC9 和 Sirtuin-1 对 Foxp3 的表达和功能有不同的影响，这表明选择性地针对单个或组合的 HDAC 可能增强 Treg 的稳定性和抑制功能。另一项研究表明，受体程序性死亡 1（PD-1），一种众所周知的 T 细胞激活抑制剂，通过抑制泛素连接酶 SCF（Skp2）的底物识别组件（Skp2）基因的转录，阻止效应 T 细胞的细胞周期进程。这些发现共同揭示了增强 Treg 或效应 T 细胞功能的新信号靶点，这可能有助于设计未来的治疗方法，无论是增加移植和自身免疫疾病中 Treg 的抑制功能，还是阻断 PD-1 功能，从而增强效应 T 细胞的抗病毒或抗肿瘤免疫反应的幅度。
