Structural studies on the formation of pore formation in the immune synapse

Perforin and the Complement Membrane Attack Complex (MAC) are related pore forming immune effectors that are deployed by the immune system to eliminate virally infected or malignant cells (perforin) and pathogenic microbes (MAC) respectively. Both systems drive host tissue damage and disease in the context of numerous difficult-to-treat inflammatory diseases and in transplant rejection. The goal of this project is to understand how perforin functions at the point of contact between an immune cell and its target (the immune synapse). In particular, we will use an in situ structural biology strategy to study the immune synapse and to identify structures within the synapse that form during immune cell recognition and killing. Complementing these studies, the project will involve using EM to study perforin structure and function ex-situ, with a goal of developing perforin inhibitors to combat immune driven diseases and bone marrow transplant rejection.