Identification of novel DC surface molecules and using them to modulate immune responses.
Dendritic cells (DC), the professional antigen-presenting cells of the immune system, not only initiate T-cell immune responses, they also regulate the type of immune response obtained. In our earlier studies we were one of the groups that demonstrated that the DC network consists of a number of discrete DC subtypes, each specialized in migratory capacity, in expression of pathogen recognition molecules such as toll-like receptors, in cytokine and chemokine production and in ability to process and “cross-present” exogenous antigens on MHC class I. As part of a study on the basis of functional differences between these DC subtypes we screened for gene-expression differences between them: this led to the identification of a number of novel DC surface molecules. These molecules have been cloned and expressed, and monoclonal antibodies (mAb) recognising them prepared. These new mAb are used to stain and recognise DC subtypes, as well as to explore their precise functions. The ligands for these DC surface molecules are being sought. A recent example of this approach is our identification of the C-type lectin-like molecule Clec9A, selectively expressed by the CD8-bearing mouse DC subset. Clec9A recognises a molecule exposed when the cell membrane is ruptured on cell death, and is involved in the way the CD8-bearing DC subtype efficiently processes and presents antigens derived from dead cells.
These novel DC surface molecules are being exploited as targets to deliver antigens to DC in vivo . Antigens are coupled to the mAb recognizing the DC surface molecule, and this shuttles the antigen efficiently to the particular DC subtype. This may result in specific tolerance in some cases if the DC are not activated. In other cases, particularly when DC activation agents are administered, this can greatly enhance the response to a vaccine antigen. Clec9A has proved a particularly effective target for immune modulation, not only enhancing T cell responses but also (via helper T cells) vastly improving antibody responses. The use of these DC surface molecules as targets to improve vaccines against malaria, influenza and HIV is being explored.