More than a million cells die every minute in an adult human body. But what actually happens to these cells? How does cell death influence all our living organs and tissues, particularly our immune system? Research into how the different types of cell death influence immunity is vital for the development of therapies based on immune system activation. In their efforts to investigate this question, scientists from the Immunobiology of Dendritic Cells Unit (Institut Pasteur/Inserm) managed to specifically activate the two types of cell death, apoptosis* and necroptosis* (programmed necrosis*), in in vitro and in vivo cell models, and to assess the related immune response.
They initially observed that necroptotic cells (induced by the activation of a protein known as RIPK1) caused a strong specific CD8+ T cell response and that they were more immunogenic than apoptotic cells. These responses were able to induce a protective immune response against a colon cancer model, for example. However, contrary to what was previously thought, the scientists then demonstrated that the release of DAMPs during necroptosis was not the only cause of this high immunogenicity; another cascade of reactions, also dependent on RIPK1, was involved. This cascade activates another pathway – the NF-kB pathway – which induces the expression of an inflammatory genetic program in dying cells.
By demonstrating that RIPK1 orchestrates the antitumor immune response through its ability to coordinate the pathways associated with cell death and inflammation simultaneously, this research pinpoints potential new targets in the fight against cancer.
Two types of death
Apoptosis is a process of programmed cell death that was long thought to be a physiological, "silent" death in immunological terms: it is a "natural" death that may be caused by cell renewal or scarring, for example.
Necrosis is accidental cell death. Cells undergoing necrosis uncontrollably release molecules known as DAMPs, which act as warning signals for the immune system.
Cells that have been infected by a microbe or that have become cancerous ultimately die and are ingested by dendritic cells which are able to recover protein fragments (antigens) from these dying cells. The dendritic cells present these antigens on their surface so that they can be recognized by the immune system, triggering the activation of CD8+ T lymphocytes that are specifically tasked with attacking cells that carry these antigens. This explains how, when a cell dies because of an infection or because it has become cancerous, the immune system can mount responses against the virus or cancer. The way the cell dies will regulate the magnitude and efficiency of such a response.
RIPK1 and NF-κB signaling in dying cells determine CD8+ T cell cross-priming potential, Science, October 16, 2015
Nader Yatim (1,2,3), Hélène Jusforgues-Saklani (1,2), Susana Orozco(4), Oliver Schulz (5), Rosa Barreira da Silva (1,2), Caetano Reis e Sousa (5), Douglas R. Green (6), Andrew Oberst (4) and Matthew L. Albert (1,2)
1 - The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015, Paris, France
2 - INSERM U818, 25 Rue du Docteur Roux, 75015, Paris, France
3 - Frontières du Vivant Doctoral School, ED474, Université Paris Diderot-Paris 7, Sorbonne Paris Cité, 8-10 rue Charles V, 75004, Paris, France
4 - Department of Immunology, University of Washington, Campus Box 358059, 750 Republican Street, Seattle, WA, USA
5 - Immunobiology Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London
WC2A 3LY, UK
6 - Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Mis à jour le 30/12/2015