St. Anna Children's Cancer Research Institute, Laboratory of Tumor Immunology, Department of Pediatrics, Medical University Vienna, Austria.
PLoS One. 2013;8(2):e54879. doi: 10.1371/journal.pone.0054879. Epub 2013 Feb 11.
The dendritic cell (DC) coordinates innate and adaptive immunity to fight infections and cancer. Our observations reveal that DCs exposed to the microbial danger signal lipopolysaccharide (LPS) in the presence of interferon-γ (IFN-γ) acquire a continuously changing activation/maturation phenotype. The DCs' initial mode of action is pro-inflammatory via up-regulation among others of the signaling molecule interleukin (IL) 12, which polarizes IFN-γ secreting type 1 helper T-cells (Th1). Within 24 hours the same DC switches from the pro- into an anti-inflammatory phenotype. This is mediated by autocrine IL-10 release and secretion of soluble IL-2 receptor alpha (sIL-2RA) molecules. T-cells, when contacted with DCs during their anti-inflammatory phase loose their proliferative capacity and develop regulatory T-cell (Treg) -like anti-inflammatory functions indicated by IL-10 secretion and elevated FoxP3 levels. Studying the kinetics of IL-12 and IL-10 expression from LPS/IFN-γ activated myeloid DCs on a single cell level confirmed these observations. When T-cells are separated from DCs within 24 hours, they are spared from the anti-inflammatory DC activity. We conclude that, in addition to differentiation of DCs into distinct subsets, the observed sequential functional phases of DC differentiation permit the fine-tuning of an immune response. A better understanding of time-kinetic DC features is required for optimally exploiting the therapeutic capacity of DCs in cancer immune therapy.
树突状细胞 (DC) 协调先天免疫和适应性免疫以对抗感染和癌症。我们的观察结果表明，在干扰素-γ (IFN-γ) 的存在下暴露于微生物危险信号脂多糖 (LPS) 的 DC 获得不断变化的激活/成熟表型。DC 的初始作用模式是通过信号分子白细胞介素 (IL) 12 的上调等方式引发炎症，这会极化 IFN-γ 分泌的 1 型辅助 T 细胞 (Th1)。在 24 小时内，相同的 DC 从促炎状态转变为抗炎表型。这是通过自分泌 IL-10 释放和可溶性 IL-2 受体 alpha (sIL-2RA) 分子的分泌来介导的。当 T 细胞在抗炎阶段与 DC 接触时，它们会失去增殖能力，并发展出类似于调节性 T 细胞 (Treg) 的抗炎功能，表现为 IL-10 分泌和 FoxP3 水平升高。在单细胞水平上研究 LPS/IFN-γ 激活的髓样 DC 中 IL-12 和 IL-10 表达的动力学证实了这些观察结果。当 T 细胞在 24 小时内与 DC 分离时，它们就不会受到抗炎性 DC 活性的影响。我们得出结论，除了 DC 分化为不同的亚群外，观察到的 DC 分化的顺序性功能阶段还允许对免疫反应进行微调。为了在癌症免疫治疗中最佳利用 DC 的治疗能力，需要更好地了解 DC 的时间动力学特征。
