The show and tell of cross-presentation

Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet. As a central conveyor of information to CD8 T cells, cross-presentation allows cross-priming of T cells which carry out robust adaptive immune responses for tumor and viral clearance. Cross-presentation can be canonical or noncanonical depending on the functional status of the transporter associated with antigen processing (TAP), which in turn influences the vesicular route of MHC-I delivery to internalized antigen and the cross-presented repertoire of peptides. Because TAP is a central node in MHC-I presentation, it is targeted by immune evasive viruses and cancers. Thus, understanding the differences between canonical and noncanonical cross-presentation may inform new therapeutic avenues against cancer and infectious disease. Defects in cross-presentation on a cellular and genetic level lead to immune-related disease progression, recurrent infection, and cancer progression. In this chapter, we review the process of cross-presentation beginning with the DC subsets that conduct cross-presentation, the signals that regulate cross-presentation, the vesicular trafficking pathways that orchestrate cross-presentation, the modes of cross-presentation, and ending with disease contexts where cross-presentation plays a role.