What we study
This image is from the excellent review Dying cells actively regulate adaptive immune responses, by our friends and collaborators Nader Yatim, Sean Cullen, and Matthew Albert.
Programmed cell death—cellular suicide—is a fundamental process required for embryonic development, tissue homeostasis, tumor suppression and immunity. We now understand that cells can die in several different ways: in addition to the well-studied process of apoptosis, cells can activate other suicide programs, such as pyroptosis and necroptosis. Importantly, apoptotic cells are rapidly cleared from the body by phagocytes, and apoptosis is generally considered a non-inflammatory or immunosuppressive event. In contrast, cells dying by pyroptosis or necroptosis release both their contents and specific cytokine signals into surrounding tissues, activating immune cells and promoting both inflammation and adaptive immunity. Pathogen infection may trigger any of these cell death programs (depending on the bug), and various viruses and bacteria encode specific inhibitors of cell death effectors. Oncogenic transformation can also lead to inhibition of cell death signaling, and re-engagement of cell death within tumors is a major goal of cancer therapies. These observations lead to one of the central hypotheses on which the Oberst lab focuses: That how a cell dies—not simply whether it dies—is a key determinant of the innate and adaptive immune response that follows.
Some of our questions:
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 (Yatim et al., Science 2015). This is an odd finding, since inflammatory transcription is an active process, while cell death is a terminal event. We are investigating how these two immunogenic events are linked, in both engineered cellular models and viral infection.
How does cell death impact the immune response to cancer?
This figure is taken from the review Comparing the effects of different cell death programs in tumor progression and immunotherapy, on which lab members Dr. Michelle Messmer and Annelise Snyder are co-first authors.
The unregulated proliferation associated with tumor growth also causes abundant cell death within the tumor microenvironment. Furthermore, the goal of all tumor therapies is to cause the death of cancer cells. Notably though, in many cases this death is via apoptosis, which may actually dampen the immune responses that have the potential to control tumor growth. We're interested in understanding how the death of tumor cells alters the state of tumor-associated immune cells, and how changing the mechanisms by which tumor cells are killed might improve the outcomes of immunotherapy approaches such as immune checkpoint blockade.
How does the "necroptotic" pathway protect the brain from viral infection?
Necroptotic cell death probably evolved to protect us from viral infection; consistent with this idea, several herpesviruses encode specific inhibitors of necroptosis. We recently found that mice lacking the key necroptotic kinases RIPK1 or RIPK3 highly susceptible to infection by the flavivirus West Nile virus, and that these animals fail to control this virus within their central nervous system (CNS). Surprisingly though, animals lacking the downstream effectors MLKL or Caspase-8 (the molecules by which RIPKs can kill cells) did not share this phenotype. This implies that there are cell death independent functions of the "necroptotic" pathway that are protective during viral infection. We described one such function as the coordination of chemokine production by neurons; without this pathway, the neurons infected with West Nile virus can't effectively recruit protective immune cells to the brain to fight the virus (Daniels et al, Cell 2017).
We're now investigating other aspects of this pathway in neurons, including how viral infection is sensed, how the RIPKs drive chemokine production, and chemokine-independent aspects of RIPK-dependent antiviral signaling. More broadly, we wonder why activation of "necroptsis" in neurons doesn't cause them to die. We also wonder how activation of this pathway might affect recover from neuroinvasive infection, and the cognitive changes that can accompany it.