Lipid peroxidation causes endosomal antigen release for cross-presentation.

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Dendritic cells (DCs) are crucial for initiating adaptive immunity by presenting antigens to T cells.
• Cross-presentation, where exogenous antigens are presented on MHC class I molecules, is vital for cytotoxic T cell responses against pathogens and cancer.
• The mechanism of antigen release from endosomes into the cytosol for cross-presentation remains incompletely understood.

Purpose of the Study:

• To elucidate the mechanism of antigen release from endosomes during cross-presentation.
• To investigate the role of reactive oxygen species (ROS) and the NOX2 complex in this process.

Main Methods:

• Utilized dendritic cells (DCs) from healthy donors and patients with chronic granulomatous disease (CGD).
• Employed ROS-generating agents and scavengers to modulate oxidative stress.
• Assessed antigen leakage from endosomes and cross-presentation efficiency.

Main Results:

• Reactive oxygen species (ROS) produced by the NADPH-oxidase complex NOX2 induce lipid peroxidation, leading to antigen release from endosomes.
• Inhibition of ROS production or scavenging radicals impaired antigen leakage and cross-presentation.
• Antigen release was enhanced by ROS-generating photosensitizers and impaired in DCs with dysfunctional NOX2.

Conclusions:

• NOX2-derived ROS directly oxidize endosomal lipids, causing antigen release essential for cross-presentation.
• This study identifies a novel cellular function for ROS in regulating immune responses.
• The findings have implications for understanding immunity against infections and cancer, and for developing immunotherapies.