Modulation of dendritic cell maturation by ribotoxic and oxidative stress

Dendritic cells (DC) are known to be vital to the immune response, priming naive T cells to antigen specific proliferation. Dendritic cells in their immature state have a unique capacity to ingest large numbers of antigens via macopinocytosis. After receiving an appropriate signal they mature to an antigen presenting and T cell stimulatory state, displaying antigens bound to MHC molecules and up-regulating expression of co-stimulatory molecules. It is now well established that DC are matured by recognition of conserved molecular pattern on pathogenic organisms, often referred to as PAMPs (pathogen associated molecular patterns). In addition DC can mature in response to inflammatory cytokines such as TNF-a and IL-1 p. In this thesis an alternative DC maturation pathway is proposed, in which DC mature in response to interference with the ribosomal machinery, particularly 28S rRNA. The stress kinases are also proposed to signal any changes in 28S rRNA status within the DC. To test this hypothesis DC are incubated with ribotoxic compounds and maturation is measured by phenotype analysis, T cell stimulation and cytokine release. The results show that ribotoxic compounds can at low doses cause partial activation of DC. The proposal is then made that this route of DC activation may signal viral infection of DC, leading to maturation in response. In addition low level redox stress is shown to act in synergy with LPS to enhance T cell proliferation and cytokine release. Finally necrotic lymphocyte treated DC are shown to enhance T cell proliferation. Therefore the conclusion is made that stress per se acts as an auxiliary mechanism of enhancing immune responses, acting in synergy with receptor driven immune activation. The 28S rRNA pathway however is proposed as a major route of viral activation of DC