Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom.
J Immunol. 2011 Oct 1;187(7):3721-9. doi: 10.4049/jimmunol.1002354. Epub 2011 Aug 29.
Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders.
阻断白细胞介素 2 受体（IL-2R）与人类抗 CD25 Abs（如达利珠单抗）的结合，可抑制人 T 细胞中的 Th2 反应。最近的鼠类研究表明，白细胞介素 2（IL-2）通过激活 STAT5 也在调节 Th2 细胞分化中发挥重要作用。为了探讨激活的 STAT5 在人源 T 细胞 Th2 分化中的作用，我们研究了 IL-2 调节 C-MAF 表达的机制。染色质免疫沉淀研究显示，IL-2 诱导 STAT5 结合到 C-MAF 启动子的特定位点。这些位点与静止 CD4 和分化的 Th2 细胞中富含染色质结构特征标记的区域相对应。与白细胞介素 6（IL-6）不同，IL-2 可诱导 CD4 T 细胞表达 C-MAF，而无需预先进行 T 细胞受体（TCR）刺激。TCR 诱导的 C-MAF 表达被达利珠单抗或 JAK3 抑制剂 R333 显著抑制。此外，IL-2 和 IL-6 协同诱导 TCR 激活的 T 细胞表达 C-MAF，表明这些细胞因子之间存在功能协同作用。最后，IL-2R 阻断显著抑制 TCR 诱导的早期 IL4 mRNA 表达和分化的 Th2 细胞中的 IL-4 细胞因子表达。因此，我们的研究结果表明，IL-2 在人源 T 细胞 Th2 分化中具有重要作用，并支持了针对 IL-2R 的治疗方法可能对过敏症具有治疗作用的观点。
