Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
PLoS One. 2012;7(8):e42430. doi: 10.1371/journal.pone.0042430. Epub 2012 Aug 3.
The type of adaptive immune response following host-fungi interaction is largely determined at the level of the antigen-presenting cells, and in particular by dendritic cells (DCs). The extent to which transcriptional regulatory events determine the decision making process in DCs is still an open question. By applying the highly structured DC-ATLAS pathways to analyze DC responses, we classified the various stimuli by revealing the modular nature of the different transcriptional programs governing the recognition of either pathogenic or commensal fungi. Through comparison of the network parts affected by DC stimulation with fungal cells and purified single agonists, we could determine the contribution of each receptor during the recognition process. We observed that initial recognition of a fungus creates a temporal window during which the simultaneous recruitment of cell surface receptors can intensify, complement and sustain the DC activation process. The breakdown of the response to whole live cells, through the purified components, showed how the response to invading fungi uses a set of specific modules. We find that at the start of fungal recognition, DCs rapidly initiate the activation process. Ligand recognition is further enhanced by over-expression of the receptor genes, with a significant correspondence between gene expression and protein levels and function. Then a marked decrease in the receptor levels follows, suggesting that at this moment the DC commits to a specific fate. Overall our pathway based studies show that the temporal window of the fungal recognition process depends on the availability of ligands and is different for pathogens and commensals. Modular analysis of receptor and signalling-adaptor expression changes, in the early phase of pathogen recognition, is a valuable tool for rapid and efficient dissection of the pathogen derived components that determine the phenotype of the DC and thereby the type of immune response initiated.
宿主与真菌相互作用后适应性免疫反应的类型在很大程度上取决于抗原呈递细胞，尤其是树突状细胞（DC）。转录调控事件在多大程度上决定了 DC 中的决策过程仍然是一个悬而未决的问题。通过应用高度结构化的 DC-ATLAS 通路来分析 DC 反应，我们通过揭示控制识别致病性或共生真菌的不同转录程序的模块化性质，对各种刺激进行了分类。通过比较受 DC 刺激和真菌细胞及纯化的单一激动剂影响的网络部分，我们可以确定每个受体在识别过程中的贡献。我们观察到，真菌的初始识别会产生一个时间窗口，在此期间，细胞表面受体的同时募集可以增强、补充和维持 DC 的激活过程。通过纯化成分对整个活细胞反应的破坏，显示了入侵真菌的反应如何使用一组特定的模块。我们发现，在真菌识别的开始阶段，DC 迅速启动激活过程。配体识别通过受体基因的过表达进一步增强，基因表达与蛋白水平和功能之间存在显著的对应关系。然后受体水平显著下降，表明此时 DC 决定了特定的命运。总的来说，我们的基于通路的研究表明，真菌识别过程的时间窗口取决于配体的可用性，并且对病原体和共生体来说是不同的。在病原体识别的早期阶段，对受体和信号转导衔接子表达变化的模块分析是快速有效地剖析决定 DC 表型并因此决定起始免疫反应类型的病原体衍生成分的有价值的工具。
