The ongoing saga of the mechanism(s) of MHC class I-restricted cross-presentation

Abstract

Cross-presentation is an MHC-I antigen processing pathway that results in the presentation of peptides from exogenous viral, bacterial, parasitic, and tumor antigens and ultimately leads to priming of naïve CD8⁺ T cells. This process involves several cellular compartments and multiple components. Successful generation of MHC-I-peptide complexes requires that these components act together in a coordinated fashion. We discuss recent findings on the source of MHC-I, the role of the TAP transporter, the importance of intracellular trafficking events, mechanisms of antigen access the cytosol, and how innate immune signals can affect presentation, with an emphasis on how these pathways compare to conventional antigen presentation and how they correlate with existing data.

Figure 1. Cross-presentation of antigens depend on well-orchestrated delivery of factors to phagosomes

Conventional as well as cross-presentation of most antigens depend on proteasomal activity. In the model shown, phagocytosed antigens may be translocated into the cytosol via a transporter (possibly involving Sec61 and/or other processes), potentially delivered to the phagosome via the ER-Golgi Intermediate Compartment (ERGIC), and degraded by cytosolic proteasomes. Processed peptides are transported back into the phagosomes for loading via TAP or an unidentified transporter, also likely acquired from the ERGIC. Antigenic peptides may be further processed by IRAP and loaded onto MHC-I, acquired from recycling endosomes. Maintenance of a near neutral pH and reduced proteolysis is achieved by delivery of NOX2 machinery from Lysosome-Related Organelles (LRO), which may also facilitate antigen entry into the cytosol.

Figure 2. To mount an effective immune response, peptide-MHC-I complexes generated by cross-presentation need to match those generated by the conventional MHC-I presentation pathway

(A) Dendritic cells phagocytose/endocytose antigens from infected tissue. (B) These dendritic cells process and present antigenic peptides, generated by cross-presentation and loaded onto MHC-I, to naïve CD8-positive T-cells, priming them. (C) The primed T-cells migrate to the infected tissue and, (D), recognize peptide-MHC-I presented by infected cells and eliminate them. An effective response requires presentation of the same peptides by DCs (involving cross-presentation) and infected/tumor cells (involving conventional MHC-I antigen presentation). Processing of antigens by the conventional pathway depends on proteasomes and in some cases ER aminopeptidases. Along with proteasomes and ERAPs, cross-presentation can also depend on IRAP and cathepsin S.