{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:06:13Z","timestamp":1790687173850,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T00:00:00Z","timestamp":1583884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["10620"],"award-info":[{"award-number":["10620"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["823.02.014"],"award-info":[{"award-number":["823.02.014"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["APERIM"],"award-info":[{"award-number":["APERIM"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Our immune system can destroy most cells in our body, an ability that needs to be tightly controlled. To prevent autoimmunity, the thymic medulla exposes developing T cells to normal \u201cself\u201d peptides and prevents any responders from entering the bloodstream. However, a substantial number of self-reactive T cells nevertheless reaches the periphery, implying that T cells do not encounter all self peptides during this negative selection process. It is unclear if T cells can still discriminate foreign peptides from self peptides they haven\u2019t encountered during negative selection. We use an \u201cartificial immune system\u201d\u2014a machine learning model of the T cell repertoire\u2014to investigate how negative selection could alter the recognition of self peptides that are absent from the thymus. Our model reveals a surprising new role for T cell cross-reactivity in this context: moderate T cell cross-reactivity should skew the post-selection repertoire towards peptides that differ systematically from self. Moreover, even some self-like foreign peptides can be distinguished provided that the peptides presented in the thymus are not too similar to each other. Thus, our model predicts that negative selection on a well-chosen subset of self peptides would generate a repertoire that tolerates even \u201cunseen\u201d self peptides better than foreign peptides. This effect would resemble a \u201cgeneralization\u201d process as it is found in learning systems. We discuss potential experimental approaches to test our theory.<\/jats:p>","DOI":"10.3390\/cells9030690","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T12:22:51Z","timestamp":1584015771000},"page":"690","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Is T Cell Negative Selection a Learning Algorithm?"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3362-5229","authenticated-orcid":false,"given":"Inge M. N.","family":"Wortel","sequence":"first","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26-28, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8756-1171","authenticated-orcid":false,"given":"Can","family":"Ke\u015fmir","sequence":"additional","affiliation":[{"name":"Theoretical Biology, Department of Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2130-691X","authenticated-orcid":false,"given":"Rob J.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Theoretical Biology, Department of Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith N.","family":"Mandl","sequence":"additional","affiliation":[{"name":"Department of Physiology, McGill University, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-9458","authenticated-orcid":false,"given":"Johannes","family":"Textor","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26-28, 6525 GA Nijmegen, The Netherlands"},{"name":"Theoretical Biology, Department of Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.cell.2006.02.001","article-title":"The Evolution of Adaptive Immune Systems","volume":"124","author":"Cooper","year":"2006","journal-title":"Cell"},{"key":"ref_2","first-page":"nrg2703","article-title":"Origin and evolution of the adaptive immune system: Genetic events and selective pressures","volume":"11","author":"Flajnik","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13139","DOI":"10.1073\/pnas.1409155111","article-title":"Diversity and clonal selection in the human T-cell repertoire","volume":"111","author":"Qi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"334395a0","DOI":"10.1038\/334395a0","article-title":"T-cell antigen receptor genes and T-cell recognition","volume":"334","author":"Davis","year":"1988","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zarnitsyna, V., Evavold, B., Schoettle, L., Blattman, J., and Antia, R. (2013). Estimating the Diversity, Completeness, and Cross-Reactivity of the T Cell Repertoire. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00485"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"ni0401","DOI":"10.1038\/86280","article-title":"Autoimmunity versus horror autotoxicus: The struggle for recognition","volume":"2","author":"Silverstein","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4049\/jimmunol.164.1.121","article-title":"Deriving Quantitative Constraints on T Cell Selection from Data on the Mature T Cell Repertoire","volume":"164","author":"Detours","year":"2000","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/S1471-4906(03)00028-0","article-title":"Quantitative constraints on the scope of negative selection","volume":"24","author":"Bonhoeffer","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.immuni.2014.07.007","article-title":"Revisiting Thymic Positive Selection and the Mature T Cell Repertoire for Antigen","volume":"41","author":"Vrisekoop","year":"2014","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.immuni.2015.05.001","article-title":"Clonal Deletion Prunes but Does Not Eliminate Self-Specific \u03b1\u03b2CD8+ T Lymphocytes","volume":"42","author":"Yu","year":"2015","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.immuni.2015.10.011","article-title":"CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather than Deletion","volume":"43","author":"Legoux","year":"2015","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.immuni.2015.11.002","article-title":"Not-So-Negative Selection","volume":"43","author":"Davis","year":"2015","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Calis, J.J.A., Boer, R.J.D., and Kesmir, C. (2012). Degenerate T-cell Recognition of Peptides on MHC Molecules Creates Large Holes in the T-cell Repertoire. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002412"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0019-9958(67)91165-5","article-title":"Language identification in the limit","volume":"10","author":"Gold","year":"1967","journal-title":"Inf. Control."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1037\/0033-295X.102.3.419","article-title":"Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory","volume":"102","author":"McClelland","year":"1995","journal-title":"Psychol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1145\/262793.262811","article-title":"Computer Immunology","volume":"40","author":"Forrest","year":"1997","journal-title":"Commun. ACM"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1126\/science.267.5199.843","article-title":"Gauging Similarity with n-Grams: Language-Independent Categorization of Text","volume":"267","author":"Damashek","year":"1995","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.4049\/jimmunol.1102661","article-title":"The Role of Naive T Cell Precursor Frequency and Recruitment in Dictating Immune Response Magnitude","volume":"188","author":"Jenkins","year":"2012","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"468","DOI":"10.3389\/fimmu.2015.00468","article-title":"Lower Affinity T Cells are Critical Components and Active Participants of the Immune Response","volume":"6","author":"Martinez","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_20","unstructured":"Castro, L.D., and Timmis, J. (2002). Artificial Immune Systems: A New Computational Intelligence Approach, Springer Science & Business Media."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1073\/pnas.90.5.1691","article-title":"Predicting the size of the T-cell receptor and antibody combining region from consideration of efficient self-nonself discrimination","volume":"90","author":"Percus","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.tcs.2010.09.022","article-title":"Negative selection algorithms on strings with efficient training and linear-time classification","volume":"412","author":"Elberfeld","year":"2011","journal-title":"Theor. Comput. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Frankild, S., Boer, R.J.D., Lund, O., Nielsen, M., and Kesmir, C. (2008). Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for \u201cHoles\u201d in the T Cell Repertoire. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001831"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16671","DOI":"10.1073\/pnas.0808081105","article-title":"How the thymus designs antigen-specific and self-tolerant T cell receptor sequences","volume":"105","author":"Jha","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"032413","DOI":"10.1103\/PhysRevE.97.032413","article-title":"How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes","volume":"97","author":"Chen","year":"2018","journal-title":"Phys. Rev. E"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2014.03.047","article-title":"Deconstructing the peptide-MHC specificity of T cell recognition","volume":"157","author":"Birnbaum","year":"2014","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.immuni.2014.12.022","article-title":"T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity","volume":"42","author":"Nelson","year":"2015","journal-title":"Immunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41589-018-0130-4","article-title":"T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability","volume":"14","author":"Riley","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive features define epitope-specific T cell receptor repertoires","volume":"547","author":"Dash","year":"2017","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/nature22976","article-title":"Identifying specificity groups in the T cell receptor repertoire","volume":"547","author":"Glanville","year":"2017","journal-title":"Nature"},{"key":"ref_31","unstructured":"Dunning, T. (1994). Statistical Identification of Language, New Mexico State University. Technical Report."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4337","DOI":"10.4049\/jimmunol.0901607","article-title":"Quantitating T Cell Cross-Reactivity for Unrelated Peptide Antigens","volume":"183","author":"Ishizuka","year":"2009","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1084\/jem.20001021","article-title":"Estimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells","volume":"195","author":"Blattman","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3718","DOI":"10.1182\/blood-2009-10-251124","article-title":"Enumeration of human antigen\u2013 specific naive CD8+ T cells reveals conserved precursor frequencies","volume":"115","author":"Alanio","year":"2010","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6731","DOI":"10.4049\/jimmunol.1000295","article-title":"Impact of TCR Reactivity and HLA Phenotype on Naive CD8 T Cell Frequency in Humans","volume":"184","author":"Legoux","year":"2010","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1128\/JVI.00093-11","article-title":"Immunodominance of HLA-A2-Restricted Hepatitis C Virus-Specific CD8+ T Cell Responses Is Linked to Na\u00efve-Precursor Frequency","volume":"85","author":"Schmidt","year":"2011","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00251-008-0341-z","article-title":"NetMHCpan, a method for MHC class I binding prediction beyond humans","volume":"61","author":"Hoof","year":"2009","journal-title":"Immunogenetics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"nri3279","DOI":"10.1038\/nri3279","article-title":"Why must T cells be cross-reactive?","volume":"12","author":"Sewell","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3389\/fimmu.2014.00013","article-title":"Theories and quantification of thymic selection","volume":"5","author":"Yates","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11833","DOI":"10.1073\/pnas.1222467110","article-title":"Quorum sensing allows T cells to discriminate between self and nonself","volume":"110","author":"Butler","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.celrep.2015.04.051","article-title":"T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens","volume":"11","author":"Voisinne","year":"2015","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"nri3667","DOI":"10.1038\/nri3667","article-title":"Positive and negative selection of the T cell repertoire: What thymocytes see (and don\u2019t see)","volume":"14","author":"Klein","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.immuni.2009.10.009","article-title":"Thymoproteasome Shapes Immunocompetent Repertoire of CD8+ T Cells","volume":"32","author":"Nitta","year":"2010","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"ncomms8484","DOI":"10.1038\/ncomms8484","article-title":"Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells","volume":"6","author":"Sasaki","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Adamopoulou, E., Tenzer, S., Hillen, N., Klug, P., Rota, I.A., Tietz, S., Gebhardt, M., Stevanovic, S., Schild, H., and Tolosa, E. (2013). Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat. Commun., 4.","DOI":"10.1038\/ncomms3039"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Schuster, H., Shao, W., Weiss, T., Pedrioli, P.G., Roth, P., Weller, M., Campbell, D.S., Deutsch, E.W., Moritz, R.L., and Planz, O. (2018). A tissue-based draft map of the murine MHC class I immunopeptidome. Sci. Data, 5.","DOI":"10.1038\/sdata.2018.157"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)81028-4","article-title":"The Repertoire of T Cells Shaped by a Single MHC\/Peptide Ligand","volume":"84","author":"Ignatowicz","year":"1996","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jain, E., Bairoch, A., Duvaud, S., Phan, I., Redaschi, N., Suzek, B.E., Martin, M.J., McGarvey, P., and Gasteiger, E. (2009). Infrastructure for the life sciences: Design and implementation of the UniProt website. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-136"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"UniProt Consortium (2011). Ongoing and future developments at the Universal Protein Resource. Nucleic Acids Res., 39, D214\u2013D219.","DOI":"10.1093\/nar\/gkq1020"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Textor, J., Dannenberg, K., and Li\u015bkiewicz, M. (2014). A Generic Finite Automata Based Approach to Implementing Lymphocyte Repertoire Models. Proceedings of the 2014 Annual Conference on Genetic and Evolutionary Computation, ACM.","DOI":"10.1145\/2576768.2598331"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/690\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:06:06Z","timestamp":1760173566000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,11]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cells9030690"],"URL":"https:\/\/doi.org\/10.3390\/cells9030690","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/403428","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,11]]}}}