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

•Requirements for epitope matching in conventional MHC-I presentation and cross-presentation.•Vacuolar and cytosolic pathways.•Proteasomal versus lysosomal proteolysis.•Regulation of trafficking.•Source of the relevant MHC-I molecules.

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.