Liu Chen, Wang Hong-Cheng, Yu Sen, Jin Rong, Tang Hui, Liu Yuan-Feng, Ge Qing, Sun Xiao-Hong, Zhang Yu
Department of Immunology, Peking University Health Science Center, Beijing, China.
Oklahoma Medical Research Foundation, Oklahoma City, OK.
J Immunol. 2014 Jul 15;193(2):663-672. doi: 10.4049/jimmunol.1302554. Epub 2014 Jun 11.
T regulatory (Treg) cells play crucial roles in the regulation of cellular immunity. The development of Treg cells depends on signals from TCRs and IL-2Rs and is influenced by a variety of transcription factors. The basic helix-loop-helix proteins are known to influence TCR signaling thresholds. Whether this property impacts Treg differentiation is not understood. In this study, we interrogated the role of basic helix-loop-helix proteins in the production of Treg cells using the CD4 promoter-driven Id1 transgene. We found that Treg cells continued to accumulate as Id1 transgenic mice aged, resulting in a significant increase in Treg cell counts in the thymus as well as in the periphery compared with wild-type controls. Data from mixed bone marrow assays suggest that Id1 acts intrinsically on developing Treg cells. We made a connection between Id1 expression and CD28 costimulatory signaling because Id1 transgene expression facilitated the formation of Treg precursors in CD28(-/-) mice and the in vitro differentiation of Treg cells on thymic dendritic cells despite the blockade of costimulation by anti-CD80/CD86. Id1 expression also allowed in vitro Treg differentiation without anti-CD28 costimulation, which was at least in part due to enhanced production of IL-2. Notably, with full strength of costimulatory signals, however, Id1 expression caused modest but significant suppression of Treg induction. Finally, we demonstrate that Id1 transgenic mice were less susceptible to the induction of experimental autoimmune encephalomyelitis, thus illustrating the impact of Id1-mediated augmentation of Treg cell levels on cellular immunity.
调节性T（Treg）细胞在细胞免疫调节中发挥着关键作用。Treg细胞的发育依赖于来自T细胞受体（TCR）和白细胞介素-2受体（IL-2R）的信号，并受到多种转录因子的影响。已知碱性螺旋-环-螺旋蛋白会影响TCR信号阈值。但这种特性是否会影响Treg细胞分化尚不清楚。在本研究中，我们利用CD4启动子驱动的Id1转基因来探究碱性螺旋-环-螺旋蛋白在Treg细胞产生中的作用。我们发现，随着Id1转基因小鼠年龄增长，Treg细胞持续积累，与野生型对照相比，胸腺和外周的Treg细胞数量显著增加。混合骨髓试验的数据表明，Id1对发育中的Treg细胞具有内在作用。我们将Id1表达与CD28共刺激信号联系起来，因为尽管抗CD80/CD86阻断了共刺激，但Id1转基因表达促进了CD28基因敲除小鼠中Treg前体的形成以及胸腺树突状细胞上Treg细胞的体外分化。Id1表达还允许在无抗CD28共刺激的情况下进行体外Treg细胞分化，这至少部分是由于白细胞介素-2的产生增加。然而，值得注意的是，在共刺激信号强度完全的情况下，Id1表达对Treg细胞诱导产生了适度但显著的抑制作用。最后，我们证明Id1转基因小鼠对实验性自身免疫性脑脊髓炎的诱导不太敏感，从而说明了Id1介导的Treg细胞水平增加对细胞免疫的影响。
