Dynamic interactions of dendritic cells - adhesive and migratory properties.

Dendritic cells (DCs) are professional antigen presenting cells. They patrol in an immature state for antigen and upon antigen encounter they mature. Mature DCs migrate from the periphery to secondary lymphoid organs, where they interact with naïve T cells to initiate an effective immune response. DCs have the potential to be used as vaccine adjuvants in immunotherapy against cancer. A better understanding of regulation of DC migration is of major importance to improve clinical efficiency of DCs when used as vaccine adjuvant to fight cancer. In this thesis, we investigated the role of (novel) adhesion molecules in DC adhesion and migration in vitro as well as after injection into cancer patients. We developed an automated cell track system to monitor the migratory behavior of individual DCs. Strikingly, immature DCs firmly adhere, whereas mature DCs are highly motile and efficiently migrate to T cell areas of lymph nodes in vivo. The differences in adhesion in vitro can be attributed to a difference in activation status of the ß1 integrin. We also demonstrate that the DC-specific molecule DC-SIGN binds to endothelial ICAM-2 and mediates rolling interactions. Our data indicate a central role for endothelial ICAM-2 in DC-specific migration from blood into the periphery and subsequently of immature DCs via lymph into lymphatics. Mature DCs are very well equipped to stimulate T cells. MHC class I and II, as well as the costimulatory molecules CD80 and CD86 are highly expressed on mature DCs. Moreover mature DCs are characterized by the expression of the maturation marker CD83. Interestingly, we show that the protein CD83 binds both immature and mature DCs and has a functional role in DC biology by regulating DC-mediated immune responses. The data presented in this thesis provide insight into DC migration and thereby give the opportunity to improve cancer vaccine effectiveness