MHC Class I antigen presentation and implications for vaccine development

Abstract

All cells generate peptides derived from their expressed genes and then display a fraction of them on the cell surface bound to MHC class I molecules through a process called antigen presentation. This process is important because it is the key pathway by which the immune system detects and then eliminates viral infections. Antigen presentation not only controls whether T cell responses will be generated, but also their magnitude, specificity and location. Although this process is essential for host defense, its underlying mechanisms are incompletely understood. The majority of MHC class I presented peptides are generated by the proteasome. Dendritic and many other leukocytes express an alternate form of the proteasome, called the immunoproteasome, that contains a distinct set of proteolytic active sites. In an infection, immunoproteasomes can be induced in most other cell types. We have generated mice that completely lack immunoproteasomes and have characterized their ability to present antigens and respond to viral infections. These mice have major changes in their repertoire of MHC class I-presented peptides and defects in antigen presentation that strongly affect T cell responses to viruses. In other studies we have been examining the source of MHC class I-presented peptides. It had been proposed that the majority of class I presented peptides derive from newly synthesized but defective proteins. We have generated experimental systems to critically test this model and results will be discussed. The implications of these studies for immune responses and vaccine development will also be discussed.