Peptidases trimming MHC class I ligands

Peptides presented by MHC class I molecules are typically produced through antigen degradation by the proteasome followed by trimming by exopeptidases. According to recent results, these include both aminopeptidases and carboxypeptidases in the cytosol and the endoplasmic reticulum. While cytosolic peptidases have a net neutral or destructive effect on MHC ligands, endoplasmic reticulum aminopeptidases are required for efficient class I loading and have a strong effect on the repertoire of peptide/MHC complexes. Cells lacking these enzymes can be eliminated both by NK cells and by CD8+ T cells recognizing complexes formed between an MHC class Ib molecule and a conserved peptide. Cross-presented peptides derived from internalized antigens can be processed by insulin-regulated aminopeptidase, the only endosomal trimming peptidase.

► Cytosolic peptidases have a net neutral or destructive impact on pMHC-I complexes. ► Carboxypeptidase trimming can occur in the cytosol and the endoplasmic reticulum. ► Endoplasmic reticulum aminopeptidases (ERAPs) shape the pMHC-I repertoire. ► ERAP-deficient cells are eliminated by NK cells and class Ib-restricted CD8 T cells. ► Cross-presented peptides are trimmed by insulin-regulated aminopeptidase.