Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, 151-742 Seoul, Republic of Korea.
BK21 Plus Program, College of Pharmacy, Seoul National University, 151-742 Seoul, Korea.
Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3106-3111. doi: 10.1073/pnas.1810254116. Epub 2019 Feb 4.
Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3 regulatory T cells (Tregs) by hydrolyzing immunogenic ATP into AMP. The molecular mechanism that drives CD39 expression on Tregs remains elusive. We found that tumor-infiltrating Tregs (Ti-Tregs) failed to up-regulate CD39 in mice lacking EBI3 subunit of IL-27 or IL-27Ra. Mixed bone marrow chimera and in vitro studies showed that IL-27 signaling in Tregs directly drives CD39 expression on Ti-Tregs in a STAT1-dependent, but STAT3- and T-bet-independent, manner. Tregs stimulated with IL-27 showed enhanced suppressive activities against CD8 T cell responses in vitro. Moreover, IL-27Ra-deficient Tregs and STAT1-deficient Tregs were less efficient than WT Tregs in suppressing antitumor immunity in vivo. CD39 inhibition significantly abolished IL-27-induced suppressive activities of Tregs. Thus, IL-27 signaling in Tregs critically contributes to protumorigenic properties of Tregs via up-regulation of CD39.
细胞外核苷酸酶 CD39 的表达通过将免疫原性的 ATP 水解为 AMP，有助于 Foxp3 调节性 T 细胞（Tregs）的抑制活性。驱动 Tregs 上 CD39 表达的分子机制仍不清楚。我们发现，缺乏 IL-27 的 EBI3 亚基或 IL-27Ra 的肿瘤浸润性 Tregs（Ti-Tregs）未能上调 CD39。混合骨髓嵌合体和体外研究表明，IL-27 信号在 Tregs 中直接以 STAT1 依赖性、但 STAT3 和 T-bet 非依赖性的方式驱动 Ti-Tregs 上 CD39 的表达。体外刺激的 Tregs 显示出增强的抑制 CD8 T 细胞反应的抑制活性。此外，与 WT Tregs 相比，IL-27Ra 缺陷型 Tregs 和 STAT1 缺陷型 Tregs 在体内抑制抗肿瘤免疫方面的效率较低。CD39 抑制显著消除了 IL-27 诱导的 Tregs 的抑制活性。因此，IL-27 信号在 Tregs 中通过上调 CD39 对 Tregs 的促肿瘤发生特性具有重要贡献。
