Presentation of Out-of-Frame Peptide/MHC Class I Complexes by a Novel Translation Initiation Mechanism

Immune surveillance by CD8 T cells requires that peptides derived from intracellular proteins be presented by MHC class I molecules on the target cell surface. Interestingly, MHC molecules can also present peptides encoded in alternate translational reading frames, some even without conventional AUG initiation codons. Using T cells to measure expression of MHC bound peptides, we identified the non-AUG translation initiation codons and established that their activity was at the level of translational rather than DNA replication or transcription mechanisms. This translation mechanism decoded the CUG initiation codon not as the canonical methionine but as the leucine residue, and its activity was independent of upstream translation initiation events. Naturally processed peptide/MHC complexes can thus arise from “noncoding” mRNAs via a novel translation initiation mechanism.