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

Abstract

To monitor the health of cells, the immune system tasks antigen-presenting cells with gathering antigens from other cells and bringing them to CD8 T cells in the form of peptides bound to MHC-I molecules. Most cells would be unable to perform this function because they use their MHC-I molecules to exclusively present peptides derived from the cell's own proteins. However, the immune system evolved mechanisms for dendritic cells and some other phagocytes to sample and present antigens from the extracellular milieu on MHC-I through a process called cross-presentation. How this important task is accomplished, its role in health and disease, and its potential for exploitation are the subject of this review.

Keywords: CD8 T lymphocytes; antigen presentation; antigen processing; dendritic cell; immune surveillance; phagosomes.

Figure 1. Classical Class I Antigen Presentation

The classical pathway monitors the self and foreign proteins that are synthesized by cells (Step 1). Expressed proteins destined for degradation are conjugated with ubiquitin (Step 2) followed by proteasomal degradation (Step 3). Long peptides undergo trimming by cytosolic peptidases. A fraction of peptides (red) are translocated into the lumen of the ER via TAP (Step 4). Some long peptides undergo trimming in the ER by ERAP Newly synthesized MHC I molecules first associate with the chaperone calnexin and then via tapasin to TAP in the PLC. After binding TAP-transported peptide (Step 5) the MHC I: peptide complexes are transported through the secretory pathway to the plasma membrane (Step 6) where they are presented to CD8+ cytotoxic T cells. Transporter associated with antigen processing (TAP), Endoplasmic reticulum aminopeptidase (ERAP), peptide loading complex (PLC), ER-Golgi intermediate compartment (ERGIC).

Figure 2. Cross-Presentation, Phagosome-to-Cytosol Pathway (PCP)

For XPT, exogenous antigen is internalized via pinocytosis, receptor-mediated endocytosis or phagocytosis (Step 1). Components of the PLC traffic to the endocytic compartment through a mechanism involving Sec22b (Step 2). MHC I molecules may also traffic to endosomes from the plasma membrane (in part via a Rab11a and SNAP-23 mechanism) or from the ER (potentially by way of CD74 or another mechanism) (Step 3). Antigen within the phagosome escapes to the cytosol either by membrane disruption or through an ERAD-like translocation (green) (Step 4). Antigen is then conjugated with ubiquitin and degraded by the proteasome (Step 5). Peptides (red) are then transported by TAP into the ER (red line, Step 6a) or back into the endocytic compartment (blue line, Step 6b). Long peptides in the ER can be further trimmed by ERAP (purple) while those in the endosome can be trimmed by IRAP (green) before binding MHC I. The peptide-MHC I complexes are then exported to the plasma membrane (Step 7). Dashed lines indicate steps in the pathway that are not fully understood. NADPH-oxidase 2 complex (NOX2 Complex), Tapasin (Tpn), Transporter associated with antigen processing (TAP), Endoplasmic reticulum aminopeptidase (ERAP), peptide loading complex (PLC), insulin-regulated aminopeptidase (IRAP), ER-Golgi intermediate compartment (ERGIC).

Figure 3. Cross-Presentation, Vacuolar Pathway

Exogenous antigen is internalized via phagocytosis, pinocytosis or receptor mediated endocytosis (Step 1). Antigen is cleaved by proteases within the endocytic compartment (primarily by cathepsins) and can be further trimmed by IRAP (Step 2). MHC I molecules are recruited either from the plasma membrane (blue line, Step 3) or from ER (red line, Step 3), presumably through similar mechanisms as in the P2C pathway. Peptide is loaded into MHC I in the endosome (Step 4) and the complexes then presented at the plasma membrane (Step 5). Dashed lines indicate steps in the pathway that are not fully understood. Insulin-regulated aminopeptidase (IRAP), ER-Golgi intermediate compartment (ERGIC).