Dendritic cell maturation after CD40 and TLR signaling

The dendritic cell (DC) serves to link the innate and adaptive arms of immunity. Their ability to respond to pathogenic threat by maturing and then presenting antigen to naive T cells has made them the focus of research aimed at studying the requirements for T cell priming. The sequential maturation of DCs in vivo, through Toll-like Receptor (TLR) followed by CD40 signaling allows for the induction of cell-mediated immune reactions in cases of infection, while at the same time maintaining self tolerance.;Signaling through CD40 in the DC results in a cascade of biochemical signaling pathways that ultimately determine the phenotype of a mature DC. One of the critical downstream signaling pathways common to both TLR and CD40 is NF-kappaB. In the past several years, evidence has mounted indicating that NF-kappaB activation occurs in two separate pathways that have been termed the canonical and non-canonical pathways. Since CD40 ligation has been shown to activate the non-canonical pathway we examined its role in DC maturation and function by utilizing a mutant mouse in which this pathway cannot be activated.;Although many of the functional impacts of DC maturation through TLR and CD40 signals have been identified in recent years, the transcriptional profile induced by these stimuli in vivo remains unknown. We undertook a series of in-depth gene array profiling experiments in order to investigate the mechanisms behind the functional phenotype of mature DCs. These studies yielded new insights into DC function and leave a useful database of TLR and CD40-driven genes in DCs.;Together these studies focus on elucidating important remaining questions relating to DC maturation. The knowledge gained from this work pulls together several important issues regarding DC function and will hopefully lead to further advances in this field.