The length distribution of class I-restricted T cell epitopes is determined by both peptide supply and MHC allele-specific binding preference

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.Fil: Trolle, Thomas. Technical University of Denmark; DinamarcaFil: McMurtrey, Curtis. Oklahoma State University; Estados UnidosFil: Sidney, John. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Bardet, Wilfried. Oklahoma State University; Estados UnidosFil: Osborn, Sean C.. Oklahoma State University; Estados UnidosFil: Kaever, Thomas. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Sette, Alessandro. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Hildebrand, Willliam H.. Oklahoma State University; Estados UnidosFil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; Argentina. Universidad Nacional de San Martín; ArgentinaFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados Unido