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

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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.