The origin and role of MHC class I-associated self-peptides

Under steady-state conditions, cell surface major histocompatibility complex (MHC) I molecules are associated with self-peptides collectively referred to as the self-MHC I immunopeptidome (SMII). The SMII regulates all key events that occur during the lifetime of CD8 T cells in the thymus and in the periphery. The SMII derives mainly from rapidly degraded proteins and contains a tissue-specific signature. Peptide-source proteins derive from all cell compartments but are enriched in RNA- and DNA-binding proteins, cyclins and cyclin-dependent kinases, ribosomal constituents, and chaperones. Cell stress, infection, and transformation can modify the repertoire of peptides in the SMII. Constitutive MHC I presentation of self-peptides is fraught with the risk of autoimmunity, and there is the need for complex self-tolerance mechanisms. However, self-peptide/MHC I complexes are essential for the development of "classic adaptive" TCRalphabeta CD8 T cells and directly contribute to CD8 T-cell responses against pathogens and transformed cells.