title: A large fraction of HLA class I ligands are proteasome-generated spliced peptides.
abstract: The proteasome generates the epitopes presented on human leukocyte antigen (HLA) class I molecules that elicit CD8+T cell responses. Reports of proteasome-generated spliced epitopes exist, but they have been regarded as rare events. Here, however, we show that the proteasome-generated spliced peptide pool accounts for one-third of the entire HLA class I immunopeptidome in terms of diversity and one-fourth in terms of abundance. This pool also represents a unique set of antigens, possessing particular and distinguishing features. We validated this observation using a range of complementary experimental and bioinformatics approaches, as well as multiple cell types. The widespread appearance and abundance of proteasome-catalyzed peptide splicing events has implications for immunobiology and autoimmunity theories and may provide a previously untapped source of epitopes for use in vaccines and cancer immunotherapy.
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. michele.mishto@charite.de j.liepe@imperial.ac.uk.
authors.forename: Juliane
authors.initials: J
authors.lastname: Liepe
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, Netherlands.|Netherlands Proteomics Centre, CH Utrecht, Netherlands.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marino
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, Netherlands.|Netherlands Proteomics Centre, CH Utrecht, Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: Jeko
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bunting
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.|Berlin Institute of Health, 10117 Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, Netherlands.|Netherlands Proteomics Centre, CH Utrecht, Netherlands.
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.affiliation: Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. michele.mishto@charite.de j.liepe@imperial.ac.uk.|Berlin Institute of Health, 10117 Berlin, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Mishto
mesh_terms: D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D019295:Computational Biology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D019154:Protein Splicing
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D046988:Proteasome Endopeptidase Complex