how a cell dies—not simply whether it dies—is a key determinant of the innate and adaptive immune response that follows. We use engineered forms of cell death proteins and knockout mouse models to understand how different forms of cell death occur, and to compare the immune response triggered by each in vivo in the context of infection, cancer, and autoimmunity. Specific questions currently under investigation include:
What are the determinants of the immune response to necroptotic cells? Necroptosis is a form of cellular suicide involving both lytic cell death and the production of inflammatory cytokines. We are investigating how these two immunogenic events are linked, in both engineered cellular models and viral infection.
How does pathogen sensing engage cell death? Activation of innate immune pattern-sensing pathways such as the Toll-like receptors, RIG-I-like receptors, NOD-like receptors or the cGAS-STING pathway can trigger immune cytokine production. These pathways can also lead to apoptosis, pyroptosis, or necroptosis, depending on the cell and tissue context in which they occur. We study the causes and consequences of these cell death programs.
Are there death-independent roles of the cell death machinery? (Yes, there are.) Mice lacking necroptotic effector proteins are highly susceptible to multiple types of viral infection. Surprisingly however, in some cases this susceptibility is not due to a failure to trigger cell death, but rather to non-death functions of these proteins in innate immune signaling.
How does activation of inflammatory cell death alter models of cancer and autoimmunity? Promoting inflammation and an immune response to dying cells may be beneficial in the context of infection or cancer, but an overexuberant immune response to dying cells can lead to autoimmunity. We have created engineered cell death effectors that allow us to induce specific forms of cell death in vivo. We are applying these systems to models of tumorigenesis, type-I diabetes, and lupus.