Non-conventional sources of peptides presented by MHC class I

Abstract

Effectiveness of immune surveillance of intracellular viruses and bacteria depends upon a functioning antigen presentation pathway that allows infected cells to reveal the presence of an intracellular pathogen. The antigen presentation pathway uses virtually all endogenous polypeptides as a source to produce antigenic peptides that are eventually chaperoned to the cell surface by MHC class I molecules. Intriguingly, MHC I molecules present peptides encoded not only in the primary open reading frames but also those encoded in alternate reading frames. Here, we review recent studies on the generation of cryptic pMHC I. We focus on the immunological significance of cryptic pMHC I, and the novel translational mechanisms that allow production of these antigenic peptides from unconventional sources.

Fig. 1

Schematic diagram of the MHC class I antigen processing pathway that culminates in display of peptide bound MHC I on the cell surface. Most antigenic peptides are derived from polypeptides synthesized in the cytoplasm by translation of open reading frames (ORF). However, many other peptides arise as defective ribosomal polypeptides (DRiPs) by translation of ORF or cryptic reading frames (RF). The polypeptides undergo proteolysis in the same compartment and are then transported into the endoplasmic reticulum (ER). In the ER, many peptides are further trimmed by aminopeptidases and assembled with the resident MHC molecules. The MHC I molecules then chaperone the peptides to the cell surface where they serve as potential ligands for the killer CD8⁺ T cell repertoire

Fig. 2

Schematic view of translational products of a typical mRNA containing untranslated regions (UTR) and the translated open reading frame (ORF). The polypeptides arise from translation of the ORF (RF0), or alternate reading frames (RF1 or RF2) by ribosomes initiating at the conventional AUG or non-conventional CUG codons. The AUG and the CUG initiation codons can be translated as the canonical methionine (M) or the leucine (L) residues, respectively. UAG is a translation termination codon. The final peptides presented by MHC molecules are shown as colored circles