Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I‐restricted presentation

The concept of distinct endogenous and exogenous pathways for generating peptides for MHC-I and MHC-II-restricted presentation to CD4+ or CD8+ T cells fits well with the bulk of experimental data. Nevertheless, evidence is emerging for alternative processing pathways that generate peptides for MHC-I-restricted presentation. Using a well characterized, particulate viral antigen of prominent medical importance (the hepatitis B surface antigen), we summarize our evidence that the efficient, endolysosomal processing of exogenous antigens can lead to peptide-loaded MHC-I molecules. In addition, we describe evidence for endolysosomal processing of mutant, stress protein-bound, endogenous antigens that liberate peptides binding to (and presented by) MHC-I molecules. The putative biological role of alternative processing of antigens generating cytotoxic T-lymphocyte-stimulating epitopes is discussed.