Regulation of Antigen Export to the Cytosol During Cross-Presentation

Abstract

Cross-priming refers to the induction of primary cytotoxic CD8⁺ T cell responses to antigens that are not expressed in antigen presenting cells (APCs) responsible for T cell priming. Cross-priming is achieved through cross-presentation of exogenous antigens derived from tumors, extracellular pathogens or infected neighboring cells on Major Histocompatibility Complex (MHC) class I molecules. Despite extensive research efforts to understand the intracellular pathways involved in antigen cross-presentation, certain critical steps remain elusive and controversial. Here we review recent advances on antigen cross-presentation, focusing on the mechanisms involved in antigen export to the cytosol, a crucial step of this pathway.

Keywords: ERAD; cross-presentation; cytosolic antigen export; dendritic cells; endosomal leakage.

Figure 1

Schematic representation of the current understanding of antigen export to the cytosol during cross-presentation. The transporter hypothesis is depicted on the left side of the figure, with complexes involved grouped according to known (for ERAD) or supposed (Hsp90 with unknown transporter) interactions. The alternative membrane disruption hypothesis is depicted on the right side of the figure. The ROS-mediated leakage part has been confirmed experimentally, while modification of endo/phagosome lipid composition, suggested by biophysical studies, is speculative and lacks functional relevance in antigen export to the cytosol.