Research

• Antigen processing
• Antiviral immunity
• Viral immune evasion

Viruses present a special problem to the immune system, since they replicate inside cells while the T cells that survey our bodies for abnormalities are on the other side of the infected cell's membrane. How do cells turn themselves inside out, so that T cells can examine their interior and decide if there is an infection? The solution is the class I major histocompatibility complex (MHC class I) system, which constantly samples all the proteins produced within a cell and presents a fingerprint of the intracellular proteins on the outside of the cells, where T cells can analyze it. This process is called "antigen processing".

MHC class I complexes present small peptides that are generated by proteolysis as proteins are destroyed and recycled. Proteasomes are required for this proteolysis, but recent findings show that peptides produced by proteasomes are often further processed by peptidases. My recent work has focused on these enzymes. As well as showing that some peptidases (e.g. thimet oligopeptidase) are destructive and reduce antigen presentation, we have found that the ER aminopeptidase ERAP1 is important in antigen presentation, and that in its absence immune responses to viruses are markedly altered, with different peptides becoming immunodominant. In my current research I am working on identifying other aminopeptidases that affect antiviral and anti-tumor immune responses, as well as determining their mechanisms of action. Ultimately I hope that this work will allow us to predict and modulate immune responses.

Although MHC class I antigen presentation is important for antiviral immunity, viruses have evolved ways of avoiding recognition through this system. Herpesviruses are particularly adept at this type of immune evasion, and have evolved molecules that attack many steps of the MHC class I antigen processing pathway. These immune evasion molecules are interesting not only as potential targets for antiviral therapy, but as basic tools to dissect and analyze antigen processing.

Other projects in my lab include the study of MHC class I folding and assembly in the endoplasmic reticulum, a process that requires many chaperones. I have characterized a mutant cell line that is defective in this process, and am using a proteomic approach to identify the mutant chaperone.