Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Solna, Sweden.
Sci Rep. 2017 Mar 9;7:43989. doi: 10.1038/srep43989.
We have previously shown that human monocyte-derived dendritic cells (DCs) acquired different characteristics in dense or sparse cell cultures. Sparsity promoted the development of IL-12 producing migratory DCs, whereas dense cultures increased IL-10 production. Here we analysed whether the density-dependent endogenous breaks could modulate DC-based vaccines. Using murine bone marrow-derived DC models we show that sparse cultures were essential to achieve several key functions required for immunogenic DC vaccines, including mobility to draining lymph nodes, recruitment and massive proliferation of antigen-specific CD4+ T cells, in addition to their TH1 polarization. Transcription analyses confirmed higher commitment in sparse cultures towards T cell activation, whereas DCs obtained from dense cultures up-regulated immunosuppressive pathway components and genes suggesting higher differentiation plasticity towards osteoclasts. Interestingly, we detected a striking up-regulation of fatty acid and cholesterol biosynthesis pathways in sparse cultures, suggesting an important link between DC immunogenicity and lipid homeostasis regulation.
我们之前已经表明，在密集或稀疏细胞培养中，人单核细胞衍生的树突状细胞（DC）获得了不同的特征。稀疏性促进了产生 IL-12 的迁移性 DC 的发育，而密集培养则增加了 IL-10 的产生。在这里，我们分析了密度依赖性内源性断裂是否可以调节基于 DC 的疫苗。使用鼠骨髓衍生的 DC 模型，我们表明稀疏培养对于实现免疫原性 DC 疫苗所需的几个关键功能是必不可少的，包括向引流淋巴结的迁移、抗原特异性 CD4+T 细胞的募集和大量增殖，以及它们的 TH1 极化。转录分析证实，稀疏培养中对 T 细胞激活的承诺更高，而从密集培养中获得的 DC 上调了免疫抑制途径的组成部分和基因，这表明它们向破骨细胞分化的可塑性更高。有趣的是，我们在稀疏培养中检测到脂肪酸和胆固醇生物合成途径的显著上调，这表明 DC 免疫原性和脂质稳态调节之间存在重要联系。
