School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
Biochem Biophys Res Commun. 2011 Apr 1;407(1):141-7. doi: 10.1016/j.bbrc.2011.02.126. Epub 2011 Mar 1.
The function and differentiation of induced regulatory T (iTreg) cells are tightly regulated by various signaling cascade. In this study, we have investigated the role of TCR signaling to induce Foxp3 gene expression in cooperation with TGF-β/IL-2 stimulation. Activation of CD4(+) T cells by TCR signaling or TGF-β/IL-2 alone failed to enhance Foxp3 expression. Only when TCR stimulation is coupled together with TGF-β/IL-2, CD4(+) T cells expressed high levels of Foxp3 by maintaining open chromatin structure around its promoter region. Under this condition, stimulation-dependent recruitment of JunB together with c-Rel enhanced Foxp3 expression. Over expression of JunB and c-Rel significantly enhanced Foxp3 promoter activity while treatment of JunB siRNA or inhibition of TCR signaling by MAPK inhibitors significantly reduced Foxp3 expression. Collectively our results suggest that TCR signaling together with TGF-β/IL-2 stimulation cooperatively enhance Foxp3 gene expression by maintaining accessible chromatin structure and by actively recruiting key transcription factors JunB and c-Rel.
诱导调节性 T(iTreg)细胞的功能和分化受到各种信号级联的严格调控。在这项研究中，我们研究了 TCR 信号转导在与 TGF-β/IL-2 刺激协同作用下诱导 Foxp3 基因表达的作用。TCR 信号转导或 TGF-β/IL-2 单独激活 CD4+T 细胞未能增强 Foxp3 的表达。只有当 TCR 刺激与 TGF-β/IL-2 偶联时，CD4+T 细胞通过维持其启动子区域周围的开放染色质结构来表达高水平的 Foxp3。在这种情况下，刺激依赖性的 JunB 和 c-Rel 的募集增强了 Foxp3 的表达。JunB 和 c-Rel 的过表达显著增强了 Foxp3 启动子活性，而 JunB siRNA 的处理或 MAPK 抑制剂对 TCR 信号的抑制显著降低了 Foxp3 的表达。总之，我们的结果表明，TCR 信号转导与 TGF-β/IL-2 刺激协同作用，通过维持可及的染色质结构和主动募集关键转录因子 JunB 和 c-Rel，共同增强 Foxp3 基因表达。
