Post-Translational Peptide Splicing and T Cell Responses

CD8⁺ T cell specificity depends on the recognition of MHC class I-epitope complexes at the cell surface. These epitopes are mainly produced via degradation of proteins by the proteasome, generating fragments of the original sequence. However, it is now clear that proteasomes can produce a significant portion of epitopes by reshuffling the antigen sequence, thus expanding the potential antigenic repertoire. MHC class I-restricted spliced epitopes have been described in tumors and infections, suggesting an unpredicted relevance of these peculiar peptides. We review current knowledge about proteasome-catalyzed peptide splicing (PCPS), the emerging rules governing this process, and the potential implications for our understanding and therapeutic use of CD8⁺ T cells, as well as mechanisms generating other non-canonical antigenic epitopes targeted by the T cell response.