N Blanchard, T Kanaseki, H Escobar, F Delebecque, NA Nagarajan, E Reyes-Vargas, DK Crockett, DH Raulet, JC Delgado, N Shastri. (2010). " Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. " J Immunol. 184, 3033-42. PMID: 20173027 DOI: 10.4049/jimmunol.0903712
The MHC class I (MHC-I) molecules ferry a cargo of peptides to the cell surface as potential ligands for CD8(+) cytotoxic T cells. For nearly 20 years, the cargo has been described as a collection of short 8-9 mer peptides, whose length and sequences were believed to be primarily determined by the peptide-binding groove of MHC-I molecules. Yet the mechanisms for producing peptides of such optimal length and composition have remained unclear. In this study, using mass spectrometry, we determined the amino acid sequences of a large number of naturally processed peptides in mice lacking the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP). We find that ERAAP-deficiency changed the oeuvre and caused a marked increase in the length of peptides normally presented by MHC-I. Furthermore, we observed similar changes in the length of viral peptides recognized by CD8(+) T cells in mouse CMV-infected ERAAP-deficient mice. In these mice, a distinct CD8(+) T cell population was elicited with specificity for an N-terminally extended epitope. Thus, the characteristic length, as well as the composition of MHC-I peptide cargo, is determined not only by the MHC-I peptide-binding groove but also by ERAAP proteolysis in the endoplasmic reticulum.