The molecular mechanisms of antigen cross-presentation for activation of CD8 T cells are only partially resolved. Ilse Dingjan, group Geert van den Bogaart, Dept. of Tumor Immunology, theme Cancer development and immune defence, now discovered a new role for lipid peroxidation in this process.
Dendritic cells (DCs) are antigen presenting cells of the immune system that take up extracellular microbes and tumor cells by endocytosis. This foreign material is subsequently degraded and derived peptide fragments are presented in MHC class II molecules to CD4 'helper' T-cells. DCs can also cross-present antigenic peptides in MHC class I to CD8 'killer' T-cells and this is essential for our immune response against cancer and pathogens that bypass normal MHC class I presentation. For cross-presentation, antigen needs to escape from endosomal compartments into the cytosol where it can be degraded by the proteasome. However, it was unknown HOW antigen escapes from endosomes.
Ilse and her co-workers now demonstrate that after antigen uptake, the NADPH oxidase NOX2 is recruited to endosomal compartments resulting in formation of large amounts of reactive oxygen species (ROS). ROS is a potent initiator of lipid peroxidation, a chain reaction that causes disruption of endosomal membranes. Lipid peroxidation promotes leakage of endosomal antigen into the cytosol, thereby increasing cross-presentation and activation of CD8 'killer' T-cells. These data show how modulation of membrane properties tune our immune responses against cancer and infectious disease.
Publication: Lipid peroxidation causes endosomal antigen release for cross-presentation. Sci Rep, 2016
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