Regulation of plasma membrane ceramide generation in dendritic cells (DCs): impact on pathogen uptake and sorting, receptor crosstalk and immune activation

作为受体刺激的脂质从而蛋白质分选的结果，膜神经酰胺平台的产生可能本质上决定了病原体的结合、摄取和加工等过程，但也调节了髓系树突状细胞(DC)中模式识别受体相关的信号通路，从而调节了免疫反应的效率和质量。我们发现，麻疹病毒(MV)与DC-SIGN结合后，DC上的鞘磷脂酶(SMase)被激活，膜上显示酸性SMase、神经酰胺和MV进入DC的受体CD150。本项目旨在确定DC及其相应受体和相关信号体中sMase激活的病原体相关机制，并评估这些相互作用对1)病原体识别受体在信号通路和转录因子激活调节中的串扰，以及2)依赖CD150的病原体摄取DC和朗格汉斯细胞(LC)并分选到不同的隔室中的后果。此外，还将分析sMase活性对DC成熟和促进T细胞激活能力的影响。这些研究将深入了解膜脂动力学如何调节DC对病原体的处理以及随后T细胞反应的诱导。

As a result of receptor-stimulated lipid and thereby protein sorting, membrane ceramide platforms are generated which may essentially determine processes such as pathogen binding, uptake and processing, yet also modulate pattern recognition receptor associated signaling pathways in myeloid dendritic cells (DCs) and thus the efficiency and quality of immune responses. We showed that ligation of DC-SIGN by measles virus (MV) causes activation of sphingomyelinases (SMases) followed by membrane display of acid SMase, ceramide and CD150, the MV entry receptor on DCs. This project aims at identifying pathogen-associated mechanisms of SMase activation in DCs and their respective receptors and associated signalosomes, and assessing the consequences of these interactions on 1) pathogen recognition receptor crosstalk in the regulation of signaling pathways and transcription factor activation, and 2) CD150-dependent pathogen uptake into DCs and Langerhans cells (LCs) and sorting into differential compartments. Moreover, consequences of SMase activity for DC maturation and ability to promote T cell activation will be analyzed. These studies will provide insight into how membrane lipid dynamics may regulate pathogen handling by DCs and subsequent induction of T cell responses.