Mechanisms of endogenous antigen processing by the MHC class II pathway: studies with viral and cellular proteins

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The immune system?s T cells recognise short protein fragments of proteins (called epitopes) that are made by various processing pathways and then displayed on the surface of the body?s cells. If a cell is infected with a virus or is cancerous then epitopes from viral or cancer-specific cellular proteins are displayed. T cells specific for these epitopes can then destroy the affected cell. Vaccines and immunotherapies are being developed that aim to harness T cells to selectively destroy virus-infected or cancerous cells in this way. It therefore becomes important to understand the processing pathways how epitopes are made, since these control the supply and composition of the epitopes displayed on the cell surface. To study how epitopes are made from proteins found in different locations within cells I have used Epstein-Barr virus (EBV) as a model. I have made T cells specific for different types of EBV protein and used these to study processing. This virus is associated with several different cancers therefore the lessons learnt from this system have direct medical impact as well as teaching us more about the immune system in general. I have found that some proteins are transferred between cells before processing while others are processed within the cell itself even though these are all located in the same cellular compartment, the nucleus. Furthermore my work also suggests that proteins within the nucleus are unavailable for processing by an important internal processing pathway called macro-autophagy. Here I intend to continue working in the EBV system to learn more about the rules governing how proteins are processed within cells. I will then extend the work to study how cellular proteins expressed in cancer cells are processed and in turn recognised by T cells and how these processes differ from viral proteins. Finally, I will study a range of inherited fatal neurological conditions, including Huntington?s disease, caused by proteins that form toxic aggregates. These aggregates may be cleared by some of the processing pathways and I wish to establish whether the rules learned from the EBV system will apply here also, whether nuclear-localised aggregates, like EBNA1, evade processing by macro-autophagy and if an alternative pathway called chaperone mediated autophagy can compensate.