Redirecting soluble antigen for MHC class I cross‐presentation during phagocytosis

Abstract

Peptides presented by MHC class I molecules are derived mostly from proteins synthesized by the antigen-presenting cell itself, while peptides presented by MHC class II molecules are derived predominantly from materials acquired by endocytosis. External antigens can also be presented by MHC class I molecules in a process referred to as cross-presentation. We report that mouse dendritic cell engagement of a phagocytic target alters endocytic processing and inhibits their proteolytic activities. During phagocytosis, endosome maturation is delayed, shows less progression towards the lysosome, and the endocytosed soluble antigen is targeted for MHC class I cross-presentation. The antigen processing in these arrested endosomes is under the control of NAPDH oxidase associated ROS. We also show that cathepsin S is responsible for the generation of the MHC class I epitope. Our results suggest that in addition to solid structure uptake, DC phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross-presentation pathway.

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules

“…In this pathway the presentation of exogenous antigens does not require proteasomes or TAP (33, 83, 84, 85). Instead, the presented peptides are generated by protein catabolism within the endocytic compartments and then loaded on MHC I molecules in these vesicles (33, 86–88) (Figure 3, Step 2). Cathepsin S has been implicated in this process for a couple of antigens both in vitro and in vivo (33, 86).…”

“…Instead, the presented peptides are generated by protein catabolism within the endocytic compartments and then loaded on MHC I molecules in these vesicles (33, 86–88) (Figure 3, Step 2). Cathepsin S has been implicated in this process for a couple of antigens both in vitro and in vivo (33, 86). Other lysosomal proteases may also help generate peptides or destroy them (33, 70, 89, 90).…”

Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

“…Most notably, the lysosomal protease cathepsin S has been found to facilitate antigen generation in DCs in the endosomal-lysosomal compartment before being presented by MHC class I molecules (Hari et al, 2015; Shen et al, 2004). In addition, in intestinal epithelial cells (IECs) as well as bone-marrow-derived antigen-presenting cells, cathepsin S is involved in antigen-presentation by MHC class II molecules, whereas cathepsin L is required for this in thymic cortical epithelial cells (Beers et al, 2005; Nakagawa et al, 1998).…”

Lipid peroxidation causes endosomal antigen release for cross-presentation

“…Antigen cross-presentation is promoted by the activity of the NADPH oxidase NOX2 10 11 12 13 14 . Already within 30 minutes after antigen uptake, NOX2 generates superoxide anions in the endosomal lumen in DCs and this production is sustained over the course of hours 10 11 12 13 14 15 16 . Superoxide anions react with protons resulting in the formation of H 2 O 2 and alkalinization of the endosomal lumen.…”

“…Thereby, NOX2 counteracts the activity of the V-ATPase and this inhibits the activation of lysosomal proteases with low pH optima, hence preserving the antigen for cross-presentation 10 11 12 . H 2 O 2 and other reactive oxygen species (ROS) produced by NOX2 activity can also oxidatively inactivate cystein cathepsins, which further inhibits degradation of antigen in endosomes of DCs 14 16 17 . ROS also react with membranes and can oxidize membrane proteins, cholesterol and particularly (poly)unsaturated lipids in a process called lipid peroxidation 18 .…”