The Length Distribution of Class I-Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele-Specific Binding Preference

• Published in: The Journal of immunology (1950) Vol. 196; no. 4; pp. 1480 - 1487
• Main Authors: Trolle, Thomas, McMurtrey, Curtis P, Sidney, John, Bardet, Wilfried, Osborn, Sean C, Kaever, Thomas, Sette, Alessandro, Hildebrand, William H, Nielsen, Morten, Peters, Bjoern
• Format: Journal Article
• Language: English
• Published: United States 15.02.2016
• Subjects: Alleles; Animals; CD8-Positive T-Lymphocytes - immunology; Epitope Mapping - methods; Epitopes, T-Lymphocyte - analysis; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Genes, MHC Class I; HeLa Cells; HLA-A Antigens - genetics; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; HLA-B Antigens - genetics; HLA-B Antigens - immunology; HLA-B Antigens - metabolism; Humans; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; Ligands; Peptides - chemistry; Peptides - immunology; Peptides - metabolism; Protein Binding
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501721

HLA class I-binding predictions are widely used to identify candidate peptide targets of human CD8(+) T cell responses. Many such approaches focus exclusively on a limited range of peptide lengths, typically 9 aa and sometimes 9-10 aa, despite multiple examples of dominant epitopes of other lengths. In this study, we examined whether epitope predictions can be improved by incorporating the natural length distribution of HLA class I ligands. We found that, although different HLA alleles have diverse length-binding preferences, the length profiles of ligands that are naturally presented by these alleles are much more homogeneous. We hypothesized that this is due to a defined length profile of peptides available for HLA binding in the endoplasmic reticulum. Based on this, we created a model of HLA allele-specific ligand length profiles and demonstrate how this model, in combination with HLA-binding predictions, greatly improves comprehensive identification of CD8(+) T cell epitopes.