Figure 1.

Processes involved in antigen processing and presentation and their effect on the generation of a diverse HLA class I peptide repertoire. Peptides for surface presentation by HLA class I molecules are generated by transcription of DNA into mRNA and subsequent translation into proteins. Here, processes such as genetic variation and epigenetic regulation at the gene level, alternative splicing and RNA editing at the transcript level, the translation of alternative open reading frames (ORFs) and non-coding regions and post-transcriptional modifications (PTMs) can enlarge the peptide repertoire. Eventually, proteins are degraded by the proteasome, generating peptides. Here, proteasomal splicing can increase peptide diversity while proteasomal degradation can also reduce the size of the repertoire by destroying some potential HLA binders. Finally, peptides are selectively conveyed via the transporter associated with antigen processing (TAP) into the lumen of the endoplasmic reticulum (ER). Here, some peptides are further trimmed by ER-associated aminopeptidases (ERAP) and then selectively associate with specific human leukocyte antigen (HLA) complexes. Eventually, stable HLA:peptide complexes are transported to the cell surface for interaction with CD8⁺ T cells. Created with BioRender.com.