Professor Matthew Albert Institut Pasteur, Paris, France
Wednesday 12th November, 4.00 p.m., Stacey Lecture Theatre 1
The danger model predicts that the way a cell dies influences the immune response, and in particular that necrotic cell death releases inflammatory damage-associated molecular patters (DAMPs) that are contained during programmed cell death (PCD). In the past decade, non-apoptotic forms of PCD have been defined, including necroptosis, a form of death morphologically similar to necrosis. Understanding how different forms of PCD influence the immune response has been hampered by the multiple programs intersecting at a molecular level, and as a result the heterogenous mixture of cell death phenotypes within a bulk cell population. We have used inducible forms of key apoptotic or necroptotic enzymes to specifically control cell death pathways, and test their impact in immunologically relevant settings. Our study demonstrates that necroptotic cells are superior in their ability to induce inflammation and recruitment of innate immune cells into the intra-peritoneal cavity. Moreover, we have shown that RIPK3-induced necroptotic cells can mediate efficient cross-priming of antigen by dendritic cells, in contrast to cells undergoing Caspase-8 induced apoptosis. Additionally, vaccination with necroptotic cells induce protective immunity to tumor challenge. Surprisingly, secondary necrotic cells or primary freeze/thaw necrotic cells, despite release of DAMPs, did not induce such a potent CD8+ T cell response, indicating that programmed necrosis provide a unique set of signals that control the cross-priming.