title: The Length Distribution of Class I-Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele-Specific Binding Preference.
abstract: 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.
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark;
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-0762-2198
authors.initials: T
authors.lastname: Trolle
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Curtis P
authors.initials: CP
authors.lastname: McMurtrey
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: John
authors.identifier: http://orcid.org/0000-0002-0987-405X
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Wilfried
authors.initials: W
authors.lastname: Bardet
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Sean C
authors.initials: SC
authors.lastname: Osborn
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-4709-6356
authors.initials: T
authors.lastname: Kaever
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark; Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, San Martín, B 1650 HMP Buenos Aires, Argentina.
authors.forename: Morten
authors.initials: M
authors.lastname: Nielsen
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and bpeters@lji.org.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
mesh_terms: D000483:Alleles; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018604:Epitope Mapping / Q000379:methods*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D005805:Genes, MHC Class I; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; D008024:Ligands; D010455:Peptides