Regulation of dendritic cell motility within stromal niches of lymph nodes. (360G-Wellcome-089009_Z_09_Z)
Without stromal cell scaffolds of lymphatic endothelium (LECs) and fibroblastic reticulum (FRCs), DCs would be unable to travel from peripheral tissues to lymph nodes (LNs) and interact with T lymphocytes. Studying the interplay between DCs and stromal cells is therefore fundamental to understanding the regulation of immune responses. I plan to characterise the nature of cell-cell contacts between DCs and stromal cells in detail, and to conduct an siRNA screen to find novel regulators of DC guid ance. These stomal cell subsets express high levels of podoplanin, the physiological ligand for CLEC-2, a receptor specifically expressed by platelets and DCs. I will evaluate the role of podoplanin, and CLEC-2 in regulating DCs motility and investigate molecular mechanisms downstream of CLEC-2 controlling DC function. The study of DC homing to LNs has focused on the up regulation of chemokine receptors such as CCR7. Although chemokine signalling is required for cells to find their direction, this alone cannot explain the acquisition of motility. Down-modulation of CCR7 reduces the numbers of T cells and DCs reaching the LN paracortex, but these cells remain motile and are simply misdirected to other compartments. Therefore, additional mechanisms regulating DC and lymphocyte motility must be at play.
£250,000 27 May 2009