Immunity to Microbes within the Cell
Protective immunity to viruses and intracellular bacteria that survive within host cells requires a specific type of white blood cells, cytotoxic T-lymphocytes (CTL). CTL recognise proteins of microbes (antigens) as short peptides that are presented on the moleecules at the cell surface (MHC class I-molecules). The recognition of these MHC-peptides triggers the toxic mechanisms of CTL, resulting in elimination of the infected cell.
Triggering immune protection
In collaboration with different international partners, we are developing safe vaccines that activate CTL against these specific pathogens and trigger immune protection. We provide novel strategies to optimise the presentation of vaccine antigens by MHC class I molecules, through our long-standing experience in studying the cellular and molecular mechanisms involved in the processing of MHC class I-presented antigens and CTL activation.
Unraveling novel proteasome activities
A second line of current research focuses on a recently discovered mechanism in antigen processing. So far, the production of MHC class I-presented peptides from intracellular antigens was thought to result mainly from degradation of antigens by a large enzyme complex, the proteasome. However, this process now appears to be more complex than so far appreciated. We have found that proteasomes not only degrade antigens, but may also paste the peptide products back together. Approximately one fourth of peptides presented by MHC class I molecules at the cell surface is generated this way. We show that several of such ‘pasted products’ are recognised by CTL responding to infection with intracellular bacteria. Our current research focusses on unraveling the role of such ‘pasted products’, as targets for CTL, in CTL-mediated immune protection to intracellular pathogens.