Dendritic cells (DC) are key regulators of the cellular immune response, which carry antigens from a site of infection in the periphery to the draining lymph nodes. The migration of DC to lymph nodes is guided through chemokines, like CCL19 (ELC) and CCL21 (SLC). Upon maturation, DC up-regulate the expression of CCR7, the receptor for these two chemokines. We recently discovered that human monocyte derived DC require prostaglandin E2 (PGE2) during maturation for efficient migration towards CCL19. In this project we will investigate how PGE2 mediates the functional coupling of DC migration to the CCR7 receptor through a detailed examination of potentially involved signal transduction modules, e.g. the analysis of PGE2-induced protein phosphorylation and the search for CCR7 associated proteins during DC maturation in the absence or presence of PGE2. We will examine the effect of PGE2 on the endocytosis and ubiquitylation of CCR7 and whether ligand binding leads to partitioning of CCR7 into caveolin or reggie 1/2 containing membrane microdomains, termed lipid rafts. Furthermore, gene chip analysis of DC matured with or without PGE2 will be performed.
This project is supported by DFG, TR-SFB 11 Konstanz-Zürich