Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation

Abstract

Macroautophagy delivers cytoplasmic constituents for lysosomal degradation. Since major histocompatibility complex (MHC) class II molecules sample peptides after lysosomal degradation for presentation to CD4⁺ T cells, it was originally described that these peptides can also originate from macroautophagy substrates. In recent years it has become clear that in addition to this canonical function of the macroautophagy machinery during MHC class II restricted antigen presentation at least parts of this machinery are also used to regulate phagocytosis of antigens, degradation of MHC class I molecules, and unconventional secretion of antigens in extracellular vesicles, including virus particles. This review discusses how both canonical and non-canonical functions of the macroautophagy machinery influence antigen presentation on MHC class I and II molecules to CD8⁺ and CD4⁺ T cells. A better understanding of the molecular mechanisms by which the macroautophagy machinery is distributed between its canonical and non-canonical functions should allow targeting of antigens to these different pathways to influence MHC restricted presentation during vaccination against infectious diseases and tumors.

Keywords: LC3-associated phagocytosis; T cells; extracellular vesicles; macroautophagy; unconventional secretion.

Figure 1

The macroautophagy machinery supports both intra- and extracellular antigen processing for MHC class II restricted presentation to CD4⁺ T cells. During LC3 associated phagocytosis (LAP) the cargo engages certain receptors, such as toll-like receptors (TLRs), including TLR2. This leads to the recruitment of the LC3 lipidation machinery (ATG5/12/16L1) via the vacuolar ATPase subunit V1A. LC3 lipidation is stabilized by the NADPH oxidase 2 (NOX2) which inhibits LC3 deconjugation by oxidation of ATG4. LC3 associated phagosomes eventually fuse with MHC class II containing compartments (MIIC). In these their cargo is degraded and loaded onto MHC class II molecules which are then transported to the cell surface for CD4⁺ T cell stimulation. Macroautophagy delivers intracellular antigens, such as ubiquitinated protein aggregates that are recruited into phagophores by autophagy receptors such as p62, with autophagosomes to MIICs. These intracellular antigens can then also be broken down by lysosomal hydrolases for loading onto MHC class II molecules.

Figure 2

MHC class I surface expression is down-regulated by the macroautophagy machinery. MHC class I molecules are loaded in the endoplasmic reticulum (ER), primarily with peptides that originate from proteasomal degradation and are then imported into the ER via the transporter associated with antigen presentation (TAP). On their way to the cell membrane from the ER, MHC class I molecules are targeted for macroautophagy by the autophagy receptor NBR1, resulting in their lysosomal degradation in pancreatic ductal adenocarcinoma (PDAC) cells. In addition, LC3 lipidation recruits parts of the internalization machinery to MHC class I molecules at the cell membrane, including AP2 associated kinase 1 (AAK1). This leads to a more rapid internalization and degradation of MHC class I molecules in dendritic cells.