Integrated genomic and proteomic analysis of signaling pathways in dendritic cell differentiation and maturation.

Dendritic cells (DCs) are antigen-presenting cells that play a major role in initiating primary immune responses. Their phenotypic and functional characteristics are intimately linked to their stage of maturation. The specific biochemical pathways and genes whose expression mediates differentiation of progenitors to DCs and their maturation are largely undefined. We recently utilized two approaches, DNA microarrays and proteomics, to analyze the expression profile of human CD14(+) blood monocytes and their derived DCs. Approximately 4% of the genes or proteins expressed were found to be regulated during DC differentiation. Most of these genes were not previously associated with DCs and included genes highly relevant to DC functions (genes involved in antigen presentation, cell adhesion and motility, lipid metabolism). Genes involved in specific signaling pathways, including IkappaBalpha, PPAR-gamma and C/EBPalpha as well as two members of the family of transcription factors, interferon regulatory factors (IRFs), were also modified. Modulation of IRF gene expression is of particular interest because of their functional roles in innate and adaptive immune responses. IRF-family members control the expression of proteins that include type-1 interferons, interleukin-12, interleukin-15, MHC molecules and adhesion molecules. They have also been found to play an important role in lymphocyte development. In contrast to DC differentiation, very few genes were modified at the transcript level during DC maturation as determined by microarray experiments. Further analysis suggested that DC maturation is largely controlled by posttranscriptional and posttranslational modifications. The use of proteomics is therefore necessary for a full comprehension of DC maturation process.