The Effect of Inflammatory Stimuli on Cryptic Peptide Presentation for Immune Surveillance

Cytolytic T cells eliminate infected cells by recognizing intracellular peptides presented by MHC class I molecules. The antigenic peptides are derived primarily from newly synthesized proteins including those produced by cryptic translation. Previous studies have shown that in addition to the canonical AUG codon, translation can be initiated at non-AUG codons. Furthermore, translation initiation at non-AUG codons such as CUG is mechanistically distinct from canonical translation initiation as it is resistant to protein synthesis inhibitors that cause global translation shutdown. Here, we show that Toll-like receptor (TLR) signaling pathways involved in pathogen recognition enhance presentation of the cryptically translated peptides. Moreover, infection of bone-marrow derived macrophages with different viruses and bacteria or treatment with pro-inflammatory cytokines also enhances presentation of cryptically translated peptides. Thus, translation and presentation of cryptic peptides may allow the immune system to detect intracellular pathogens that inhibit host translation and presentation of peptides from conventional sources