{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:35Z","timestamp":1792789295295,"version":"4.5.0"},"reference-count":130,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rhodes Trust and the National Institutes of Health (NIH) Oxford-Cambridge Scholars Program","id":[{"id":"https:\/\/ror.org\/03thhsh17","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cancer Research UK (CRUK) PhD Studentship","id":[{"id":"https:\/\/ror.org\/054225q67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"UK Medical Research Council","award":["MR\/X020746\/1"],"award-info":[{"award-number":["MR\/X020746\/1"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The major histocompatibility complex class I (MHC-I) immunopeptidome is dynamic and determined by numerous biochemical and cellular features. Computational tools to predict peptide\u2013MHC-I binding focus on the affinity of a specific peptide\u2013MHC interaction; separate tools predict complex stability or presentation. Methods used to define the immunopeptidome may preferentially recover stable complexes, and presentation predictors trained on those data may inherit that bias. However, peptides that dissociate rapidly but are generated at high rates could reach surface densities sufficient for CD8+ T cell recognition. Here, we examine evidence relevant to these fast-dissociating high-supply (FDHS) peptides and develop a two-axis model, whereby peptide supply is considered alongside stability. We examine how defective ribosomal products and ribosome-associated quality control supply peptides for MHC-I loading. We set out the limits of tapasin-mediated editing and compare the model with the binding, stability and presentation predictors now in use. Experiments have linked peptide abundance and complex stability to relative presentation, but the extent of compensation for endogenous FDHS peptides remains to be quantified. We present experimental systems to test the magnitude and limits of this compensation, specifying the key measurements. We also propose that FDHS ligands generated under tumour-specific translational stress could be less constrained by central tolerance if their presentation is insufficient during thymic selection. We believe this model has implications for understanding the broader immunopeptidome, how it contributes to innate and adaptive immunity, and designing better immunotherapies.<\/jats:p>","DOI":"10.3390\/cells15191735","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:09:08Z","timestamp":1790161748000},"page":"1735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fast-Dissociating High-Supply Peptides as Contributors to MHC-I Antigen Presentation"],"prefix":"10.3390","volume":"15","author":[{"given":"Om H.","family":"Gandhi","sequence":"first","affiliation":[{"name":"Centre for Immuno-Oncology, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8306-009X","authenticated-orcid":false,"given":"Michael E.","family":"Bryan","sequence":"additional","affiliation":[{"name":"Centre for Immuno-Oncology, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3407-9661","authenticated-orcid":false,"given":"Malcolm J. W.","family":"Sim","sequence":"additional","affiliation":[{"name":"Centre for Immuno-Oncology, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Elliott","sequence":"additional","affiliation":[{"name":"Centre for Immuno-Oncology, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class I and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev-immunol-032712-095910","article-title":"Pathways of antigen processing","volume":"31","author":"Blum","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.it.2016.08.010","article-title":"Present Yourself! By MHC Class I and MHC Class II Molecules","volume":"37","author":"Rock","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11737","DOI":"10.1073\/pnas.0306294101","article-title":"Tapasin enhances MHC class I peptide presentation according to peptide half-life","volume":"101","author":"Howarth","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S1074-7613(02)00304-7","article-title":"Optimization of the MHC class I peptide cargo is dependent on tapasin","volume":"16","author":"Williams","year":"2002","journal-title":"Immunity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1158\/2326-6066.CIR-13-0227","article-title":"HLA-binding properties of tumor neoepitopes in humans","volume":"2","author":"Fritsch","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni1058","article-title":"T cell killing does not require the formation of a stable mature immunological synapse","volume":"5","author":"Purbhoo","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nature01074","article-title":"ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum","volume":"419","author":"Serwold","year":"2002","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/ni1409","article-title":"In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides","volume":"8","author":"Hammer","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5839","DOI":"10.4049\/jimmunol.1300220","article-title":"Induction of protective antitumor immunity through attenuation of ERAAP function","volume":"190","author":"James","year":"2013","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1128\/JVI.74.8.3486-3493.2000","article-title":"A previously unrecognized H-2Db-restricted peptide prominent in the primary influenza A virus-specific CD8+ T-cell response is much less apparent following secondary challenge","volume":"74","author":"Belz","year":"2000","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1084\/jem.20022151","article-title":"Differential antigen presentation regulates the changing patterns of CD8+ T cell immunodominance in primary and secondary influenza virus infections","volume":"198","author":"Crowe","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Boulanger, D.S.M., Eccleston, R.C., Phillips, A., Coveney, P.V., Elliott, T., and Dalchau, N. (2018). A Mechanistic Model for Predicting Cell Surface Presentation of Competing Peptides by MHC Class I Molecules. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01538"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.immuni.2017.02.007","article-title":"Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction","volume":"46","author":"Abelin","year":"2017","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.4049\/jimmunol.1600808","article-title":"Unsupervised HLA Peptidome Deconvolution Improves Ligand Prediction Accuracy and Predicts Cooperative Effects in Peptide-HLA Interactions","volume":"197","author":"Gfeller","year":"2016","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41587-019-0322-9","article-title":"A large peptidome dataset improves HLA class I epitope prediction across most of the human population","volume":"38","author":"Sarkizova","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/351290a0","article-title":"Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules","volume":"351","author":"Falk","year":"1991","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1126\/science.1546328","article-title":"Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry","volume":"255","author":"Hunt","year":"1992","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1038\/s41467-020-16588-9","article-title":"Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4\/6 inhibition","volume":"11","author":"Stopfer","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1038\/s41596-019-0133-y","article-title":"Mass spectrometry-based identification of MHC-bound peptides for immunopeptidomics","volume":"14","author":"Purcell","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6295","DOI":"10.1021\/acs.jproteome.5c00449","article-title":"Data-Independent Immunopeptidomics Discovery of Low-Abundant Bacterial Epitopes","volume":"24","author":"Willems","year":"2025","journal-title":"J. Proteome Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5048","DOI":"10.4049\/jimmunol.1000134","article-title":"Differential suppression of tumor-specific CD8+ T cells by regulatory T cells","volume":"185","author":"James","year":"2010","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"ltaa001","DOI":"10.1093\/immadv\/ltaa001","article-title":"Protective low-avidity anti-tumour CD8+ T cells are selectively attenuated by regulatory T cells","volume":"1","author":"Sugiyarto","year":"2021","journal-title":"Immunother. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e007114","DOI":"10.1136\/jitc-2023-007114","article-title":"Reactivation of low avidity tumor-specific CD8+ T cells associates with immunotherapeutic efficacy of anti-PD-1","volume":"11","author":"Sugiyarto","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cole, D.K., Fuller, A., Dolton, G., Zervoudi, E., Legut, M., Miles, K., Blanchfield, L., Madura, F., Holland, C.J., and Bulek, A.M. (2017). Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01503"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1126\/science.279.5359.2103","article-title":"Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA","volume":"279","author":"Ogg","year":"1998","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.4049\/jimmunol.156.9.3308","article-title":"Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability","volume":"156","author":"Visseren","year":"1996","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1073\/pnas.1914401117","article-title":"Role for ribosome-associated quality control in sampling proteins for MHC class I-mediated antigen presentation","volume":"117","author":"Trentini","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.molcel.2018.12.020","article-title":"Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance","volume":"73","author":"Wei","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1073\/pnas.1416543112","article-title":"The first step of peptide selection in antigen presentation by MHC class I molecules","volume":"112","author":"Garstka","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1073\/pnas.1201586109","article-title":"Promiscuous binding of extracellular peptides to cell surface class I MHC protein","volume":"109","author":"Eisen","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/eji.201141774","article-title":"Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity","volume":"42","author":"Harndahl","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.4049\/jimmunol.1600582","article-title":"Pan-Specific Prediction of Peptide-MHC Class I Complex Stability, a Correlate of T Cell Immunogenicity","volume":"197","author":"Rasmussen","year":"2016","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7890","DOI":"10.4049\/jimmunol.178.12.7890","article-title":"A quantitative analysis of the variables affecting the repertoire of T cell specificities recognized after vaccinia virus infection","volume":"178","author":"Assarsson","year":"2007","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Calis, J.J.A., Maybeno, M., Greenbaum, J.A., Weiskopf, D., De Silva, A.D., Sette, A., Ke\u015fmir, C., and Peters, B. (2013). Properties of MHC class I presented peptides that enhance immunogenicity. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003266"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1038\/ni860","article-title":"The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8\u20139 residues","volume":"3","author":"York","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/eji.200737832","article-title":"Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide-MHC class I complexes","volume":"38","author":"Thirdborough","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.4049\/jimmunol.1500654","article-title":"ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules","volume":"197","author":"Nagarajan","year":"2016","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.immuni.2013.08.036","article-title":"A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4+ T cells","volume":"39","author":"Huang","year":"2013","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/375148a0","article-title":"Serial triggering of many T-cell receptors by a few peptide-MHC complexes","volume":"375","author":"Valitutti","year":"1995","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/nature08746","article-title":"TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity","volume":"463","author":"Huppa","year":"2010","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nri3254","article-title":"Cross-presentation by dendritic cells","volume":"12","author":"Joffre","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Embgenbroich, M., and Burgdorf, S. (2018). Current Concepts of Antigen Cross-Presentation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01643"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3174","DOI":"10.1002\/eji.201242606","article-title":"Different affinity windows for virus and cancer-specific T-cell receptors: Implications for therapeutic strategies","volume":"42","author":"Aleksic","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sim, M.J.W., and Sun, P.D. (2022). T Cell Recognition of Tumor Neoantigens and Insights Into T Cell Immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.833017"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/85286","article-title":"Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex","volume":"2","author":"Kalergis","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14928","DOI":"10.1038\/srep14928","article-title":"Selector function of MHC I molecules is determined by protein plasticity","volume":"5","author":"Bailey","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.coi.2021.06.016","article-title":"The role of MHC I protein dynamics in tapasin and TAPBPR-assisted immunopeptidome editing","volume":"70","author":"Elliott","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/346476a0","article-title":"Empty MHC class I molecules come out in the cold","volume":"346","author":"Ljunggren","year":"1990","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/s41467-020-14862-4","article-title":"Structures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection","volume":"11","author":"Anjanappa","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e40126","DOI":"10.7554\/eLife.40126","article-title":"TAPBPR mediates peptide dissociation from MHC class I using a leucine lever","volume":"7","author":"Ilca","year":"2018","journal-title":"Elife"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Dalchau, N., Phillips, A., Goldstein, L.D., Howarth, M., Cardelli, L., Emmott, S., Elliott, T., and Werner, J.M. (2011). A peptide filtering relation quantifies MHC class I peptide optimization. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002144"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"W449","DOI":"10.1093\/nar\/gkaa379","article-title":"NetMHCpan-4.1 and NetMHCIIpan-4.0: Improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data","volume":"48","author":"Reynisson","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.cels.2020.06.010","article-title":"MHCflurry 2.0: Improved Pan-Allele Prediction of MHC Class I-Presented Peptides by Incorporating Antigen Processing","volume":"11","author":"Rubinsteyn","year":"2020","journal-title":"Cell Syst."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/imm.12160","article-title":"NetMHCstab\u2014Predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery","volume":"141","author":"Rasmussen","year":"2014","journal-title":"Immunology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"15924","DOI":"10.1038\/ncomms15924","article-title":"Structural and regulatory diversity shape HLA-C protein expression levels","volume":"8","author":"Kaur","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Boulanger, D.S.M., Douglas, L.R., Duriez, P.J., Kang, Y., Dalchau, N., James, E., and Elliott, T. (2022). Tapasin-mediated editing of the MHC I immunopeptidome is epitope specific and dependent on peptide off-rate, abundance, and level of tapasin expression. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.956603"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.4049\/jimmunol.1403234","article-title":"Relative expression levels of the HLA class-I proteins in normal and HIV-infected cells","volume":"194","author":"Apps","year":"2015","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/imr.12325","article-title":"Newtonian cell interactions shape natural killer cell education","volume":"267","author":"Goodridge","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.it.2024.10.006","article-title":"The peptide selectivity model: Interpreting NK cell KIR-HLA-I binding interactions and their associations to human diseases","volume":"45","author":"Sim","year":"2024","journal-title":"Trends Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"iqaf003","DOI":"10.1093\/oxfimm\/iqaf003","article-title":"Peptide-specific natural killer cell receptors","volume":"6","author":"Sim","year":"2025","journal-title":"Oxf. Open Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1084\/jem.181.6.2085","article-title":"Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA","volume":"181","author":"McCutcheon","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1073\/pnas.1815239116","article-title":"Most viral peptides displayed by class I MHC on infected cells are immunogenic","volume":"116","author":"Croft","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"12826","DOI":"10.1073\/pnas.1921964117","article-title":"High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D","volume":"117","author":"Sim","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E1591","DOI":"10.1073\/pnas.1321902111","article-title":"The nature and extent of contributions by defective ribosome products to the HLA peptidome","volume":"111","author":"Bourdetsky","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S1074-7613(03)00051-7","article-title":"Quantitating protein synthesis, degradation, and endogenous antigen processing","volume":"18","author":"Princiotta","year":"2003","journal-title":"Immunity"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1074\/mcp.M114.042812","article-title":"Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation","volume":"14","author":"Jensen","year":"2015","journal-title":"Mol. Cell Proteom."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.4049\/jimmunol.157.5.1823","article-title":"Defective ribosomal products (DRiPs): A major source of antigenic peptides for MHC class I molecules?","volume":"157","author":"Yewdell","year":"1996","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/35008096","article-title":"Rapid degradation of a large fraction of newly synthesized proteins by proteasomes","volume":"404","author":"Schubert","year":"2000","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.it.2006.06.008","article-title":"The DRiP hypothesis decennial: Support, controversy, refinement and extension","volume":"27","author":"Yewdell","year":"2006","journal-title":"Trends Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/35008103","article-title":"The major substrates for TAP in vivo are derived from newly synthesized proteins","volume":"404","author":"Reits","year":"2000","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e181","DOI":"10.1182\/blood-2012-02-412593","article-title":"MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements","volume":"119","author":"Granados","year":"2012","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/msb.2011.68","article-title":"The MHC I immunopeptidome conveys to the cell surface an integrative view of cellular regulation","volume":"7","author":"Caron","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eade7890","DOI":"10.1126\/sciadv.ade7890","article-title":"Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation","volume":"9","author":"Mamrosh","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.cell.2016.12.004","article-title":"Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer","volume":"168","author":"Bettigole","year":"2017","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e70263","DOI":"10.1002\/mco2.70263","article-title":"Endoplasmic Reticulum Stress in Cancer","volume":"6","author":"Zhou","year":"2025","journal-title":"MedComm"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"102329","DOI":"10.1016\/j.coi.2023.102329","article-title":"Tumor immune evasion through loss of MHC class-I antigen presentation","volume":"83","author":"Sari","year":"2023","journal-title":"Curr. Opin. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nsmb.3147","article-title":"Ribosome-associated protein quality control","volume":"23","author":"Brandman","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41580-019-0118-2","article-title":"Mechanisms and functions of ribosome-associated protein quality control","volume":"20","author":"Joazeiro","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/s41467-020-14968-9","article-title":"Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes","volume":"11","author":"Chong","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1074-7613(00)80161-2","article-title":"Dissecting the multifactorial causes of immunodominance in class I-restricted T cell responses to viruses","volume":"12","author":"Chen","year":"2000","journal-title":"Immunity"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/sj.icb.7100026","article-title":"A question of self-preservation: Immunopathology in influenza virus infection","volume":"85","author":"Kedzierska","year":"2007","journal-title":"Immunol. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/ni942","article-title":"A structural basis for immunodominant human T cell receptor recognition","volume":"4","author":"McMichael","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nm1520","article-title":"CD8+ T-cell responses to different HIV proteins have discordant associations with viral load","volume":"13","author":"Kiepiela","year":"2007","journal-title":"Nat. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.4049\/jimmunol.178.5.2746","article-title":"Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression","volume":"178","author":"Sacha","year":"2007","journal-title":"J. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.4049\/jimmunol.172.9.5249","article-title":"The HIV-1 HLA-A2-SLYNTVATL is a help-independent CTL epitope","volume":"172","author":"Bisikirska","year":"2004","journal-title":"J. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"28232","DOI":"10.1073\/pnas.2013554117","article-title":"HLA tapasin independence: Broader peptide repertoire and HIV control","volume":"117","author":"Bashirova","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","first-page":"2486","article-title":"Proteins encoded by the human c-myc oncogene: Differential expression in neoplastic cells","volume":"4","author":"Hann","year":"1984","journal-title":"Mol. Cell Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1128\/MCB.20.7.2423-2435.2000","article-title":"C-Myc proteolysis by the ubiquitin-proteasome pathway: Stabilization of c-Myc in Burkitt\u2019s lymphoma cells","volume":"20","author":"Gregory","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.cell.2012.03.003","article-title":"MYC on the path to cancer","volume":"149","author":"Dang","year":"2012","journal-title":"Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nrc3090","article-title":"Cyclin D as a therapeutic target in cancer","volume":"11","author":"Musgrove","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1101\/gad.12.22.3499","article-title":"Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization","volume":"12","author":"Diehl","year":"1998","journal-title":"Genes Dev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1101\/gad.10.12.1443","article-title":"The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3","volume":"10","author":"Yost","year":"1996","journal-title":"Genes Dev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1093\/emboj\/16.13.3797","article-title":"Beta-catenin is a target for the ubiquitin-proteasome pathway","volume":"16","author":"Aberle","year":"1997","journal-title":"EMBO J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/S0960-9822(98)70280-5","article-title":"Evidence for successive peptide binding and quality control stages during MHC class I assembly","volume":"8","author":"Lewis","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S1074-7613(00)80558-0","article-title":"HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading","volume":"8","author":"Peh","year":"1998","journal-title":"Immunity"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1021\/acs.biochem.7b01307","article-title":"Protein Plasticity and Peptide Editing in the MHC I Antigen Processing Pathway","volume":"57","author":"Elliott","year":"2018","journal-title":"Biochemistry"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Darley, R., Illing, P.T., Duriez, P., Bailey, A., Purcell, A.W., van Hateren, A., and Elliott, T. (2025). Evidence of focusing the MHC class I immunopeptidome by tapasin. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1563789"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e1274476","DOI":"10.1080\/2162402X.2016.1274476","article-title":"Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition","volume":"6","author":"Shionoya","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1126\/science.aao6001","article-title":"Structure of the TAPBPR-MHC I complex defines the mechanism of peptide loading and editing","volume":"358","author":"Thomas","year":"2017","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"10238","DOI":"10.1038\/ncomms10238","article-title":"Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames","volume":"7","author":"Laumont","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"eaau5516","DOI":"10.1126\/scitranslmed.aau5516","article-title":"Noncoding regions are the main source of targetable tumor-specific antigens","volume":"10","author":"Laumont","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41587-022-01464-2","article-title":"Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors","volume":"41","author":"Kacen","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1126\/science.aaf4384","article-title":"A large fraction of HLA class I ligands are proteasome-generated spliced peptides","volume":"354","author":"Liepe","year":"2016","journal-title":"Science"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1074\/mcp.RA118.000877","article-title":"Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome","volume":"17","author":"Mylonas","year":"2018","journal-title":"Mol. Cell Proteom."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"11572","DOI":"10.1073\/pnas.1104104108","article-title":"Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation","volume":"108","author":"Apcher","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1074\/mcp.M900566-MCP200","article-title":"Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules","volume":"9","author":"Granados","year":"2010","journal-title":"Mol. Cell Proteom."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.cell.2017.10.001","article-title":"Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution","volume":"171","author":"McGranahan","year":"2017","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/nbt.3344","article-title":"Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes","volume":"33","author":"Shukla","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1126\/science.aao4572","article-title":"Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy","volume":"359","author":"Chowell","year":"2018","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature24473","article-title":"A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy","volume":"551","author":"Riaz","year":"2017","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1042\/BST20220782","article-title":"Advancing our knowledge of antigen processing with computational modelling, structural biology, and immunology","volume":"51","author":"Turner","year":"2023","journal-title":"Biochem. Soc. Trans."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Bassani-Sternberg, M., Chong, C., Guillaume, P., Solleder, M., Pak, H., Gannon, P.O., Kandalaft, L.E., Coukos, G., and Gfeller, D. (2017). Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity. PLoS Comput. Biol., 13.","DOI":"10.1101\/098780"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"100194","DOI":"10.1016\/j.xcrm.2021.100194","article-title":"Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting","volume":"2","author":"Schmidt","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cels.2022.12.002","article-title":"Improved predictions of antigen presentation and TCR recognition with MixMHCpred2.2 and PRIME2.0 reveal potent SARS-CoV-2 CD8+ T-cell epitopes","volume":"14","author":"Gfeller","year":"2023","journal-title":"Cell Syst."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/371626a0","article-title":"Three-dimensional structure of a peptide extending from one end of a class I MHC binding site","volume":"371","author":"Collins","year":"1994","journal-title":"Nature"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/ni1257","article-title":"T cell receptor recognition of a \u2018super-bulged\u2019 major histocompatibility complex class I-bound peptide","volume":"6","author":"Tynan","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.it.2005.11.001","article-title":"Have we cut ourselves too short in mapping CTL epitopes?","volume":"27","author":"Burrows","year":"2006","journal-title":"Trends Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1182\/blood-2012-06-437202","article-title":"Peptide length determines the outcome of TCR\/peptide-MHCI engagement","volume":"121","author":"Miles","year":"2013","journal-title":"Blood"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1126\/science.1141915","article-title":"Regulation of CD8+ T cell development by thymus-specific proteasomes","volume":"316","author":"Murata","year":"2007","journal-title":"Science"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/ncomms3039","article-title":"Exploring the MHC-peptide matrix of central tolerance in the human thymus","volume":"4","author":"Adamopoulou","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-020-03054-1","article-title":"Anti-tumour immunity induces aberrant peptide presentation in melanoma","volume":"590","author":"Bartok","year":"2021","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/s41590-024-01899-6","article-title":"Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes","volume":"25","author":"You","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.1198687","article-title":"Innate or adaptive immunity? The example of natural killer cells","volume":"331","author":"Vivier","year":"2011","journal-title":"Science"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/imr.12422","article-title":"Autophagy proteins in antigen processing for presentation on MHC molecules","volume":"272","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1126\/science.1104904","article-title":"Endogenous MHC class II processing of a viral nuclear antigen after autophagy","volume":"307","author":"Paludan","year":"2005","journal-title":"Science"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"6889","DOI":"10.1158\/0008-5472.CAN-08-0161","article-title":"Efficient cross-presentation depends on autophagy in tumor cells","volume":"68","author":"Li","year":"2008","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1735\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:27:36Z","timestamp":1790310456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":130,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191735"],"URL":"https:\/\/doi.org\/10.3390\/cells15191735","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}