The Influence of Dendritic Cells On The Differentiation of T Helper Cells.

Dendritic cells play a central role in the control of immune responses. They are unique among antigen presenting cells in their ability to stimulate naive T cells and thereby initiate primary immune responses. Polarised T helper cell subsets have been implicated in autoimmune and allergic conditions in humans and it is important to understand how such immune responses develop. Dendritic cells are known to induce IFNγ producing cells via their secretion of EL12 but little is known of their ability to promote Th2 responses. The work presented in this thesis investigated conditions in which dendritic cells modulate the cytokine profile of naive T helper cells. Dendritic cells were generated in vitro from cord blood derived CD34+ progenitor cells. They were characterised in their immature resting state and following activation by lipopolysaccharide or by crosslinking surface CD40 molecules. Mature dendritic cells increased their expression of surface co-stimulatory and histocompatibility molecules, secreted higher levels of inflammatory cytokines and increased their capacity to stimulate CD4+ T cell proliferation. Inhibition of NFkB activation prevented lipopolysaccharide-induced maturation of dendritic cells. Activated dendritic cells induced IFNγ production from CD4+ T cells. However, when dendritic cells were treated with IL4, the glucocorticoid dexamethasone or house dust mite allergens prior to activation, IFNγ production by T cells was inhibited. The IL4 or glucocorticoid effect could be explained by their inhibition of IL12 production by activated dendritic cells. In contrast, IL12 production by activated dendritic cells was unaffected by treatment with house dust mite allergens. Furthermore, house dust mite allergens did not induce secretion of antiinflammatory cytokines such as IL4, IL10, IL13 or TGFβ by dendritic cells. Investigations using cDNA arrays did not reveal differential gene expression by house dust mite treated-dendritic cells but brought to light expression of genes that have not been previously reported in dendritic cells