Plasticity in gene expression programmes of dendritic cells responding to antigens
Dendritic cells (DCs) are professional antigen presenting cells whose function is to initiate and shape an appropriate adaptive immune response. This requires an ability to distinguish differences between whole pathogens, in order to orchestrate effective downstream immunological outcomes. However, cellular re-programming of DC functions during these events are not well understood. A paradigm of dendritic cell biology is that DCs have two modes of function that relate to their differentiation states. An immature DC functions as an immune sentinel, to monitor and interrogate its surroundings for pathogens. Encounter with such stimuli results in a process termed "maturation", where DCs acquire the properties of effective antigen presenting cells. However, this process of differentiation is complex. In this thesis, gene expression profiling of DCs exposed to pathogen components has revealed three distinct phases of maturation, with statistically significant expression of subsets of genes characterising these phases. Transcriptional regulation of the signalling pathways involving p38 and ERK MAP kinases important to DC function were identified. Specific inhibitors of p38 and ERK confirmed their differential role in DC maturation, with p38 activity being necessary for the initiation of DC maturation, whilst ERK activity persists to maintain DC survival. Concurrent with the core maturation process is the DCs' ability to differentially respond to pathogens. Gene expression analysis of DCs exposed to whole viruses supports the model of DC plasticity to different pathogenic stimuli. Using exploratory cluster analysis and a novel vector algebra method, core and pathogen-specific gene expression programmes were identified. The programmes involving the differential regulation of cytokines were confirmed at the transcript level and at the protein level. Together these data show that DCs mature to effective antigen presenting cells via an orchestrated pattern of at least three gene expression programmes. Superimposed on this core maturation response are pathogen-specific transcriptional programmes. Therefore, we conclude that DCs can translate different pathogenic stimuli into core DC maturation and pathogen-specific responses that together shape an appropriate adaptive immune response.