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This diversity arises from both promiscuous gene expression and specialised differentiation programmes, including thymic mimetic\u2010cell populations, and is largely shaped by\n                    <jats:italic>AIRE<\/jats:italic>\n                    \/\n                    <jats:italic>Aire<\/jats:italic>\n                    and\n                    <jats:italic>FEZF2<\/jats:italic>\n                    \/\n                    <jats:italic>Fezf2<\/jats:italic>\n                    . Although the roles of\n                    <jats:italic>Aire<\/jats:italic>\n                    and\n                    <jats:italic>Fezf2<\/jats:italic>\n                    in regulating peripheral tissue antigen transcription are well established, a critical conceptual gap remains regarding how transcriptional promiscuity is translated into the repertoire of peptides presented by major histocompatibility complex class II (MHC\u2010II) molecules. In this review and perspective, we synthesize knowledge on mTEC biology,\n                    <jats:italic>Aire<\/jats:italic>\n                    \u2010 and\n                    <jats:italic>Fezf2<\/jats:italic>\n                    \u2010dependent transcriptional programmes, and advances in immunopeptidomics. We discuss regulatory layers that decouple mRNA abundance from peptide presentation and highlight how single\u2010cell transcriptomics and mass spectrometry\u2013based immunopeptidomics provide complementary insights into mTEC heterogeneity and antigenic output. We argue that integrating these approaches is essential to understand central tolerance mechanistically and to explain selective defects in thymic self\u2010antigen presentation. This framework offers a refined basis for interpreting autoimmune disease origins and guiding antigen\u2010focused therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1111\/imm.70176","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T01:41:52Z","timestamp":1784857312000},"page":"337-349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Aire<\/i>\n                    and\n                    <i>Fezf2<\/i>\n                    Shape the Medullary Thymic Epithelial Cell Immunopeptidome for Central Tolerance"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-140X","authenticated-orcid":false,"given":"Geraldo Aleixo","family":"Passos","sequence":"first","affiliation":[{"name":"Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, Ribeir\u00e3o Preto School of Dentistry University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"},{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitor Marcel","family":"Fa\u00e7a","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Proteomics, Department of Biochemistry and Immunology, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Antonio","family":"Donadi","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology, Department of Medicine, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula","family":"Masson","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Proteomics, Department of Biochemistry and Immunology, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Crippa","family":"Coletto","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Ronconi","family":"Roza","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School University of S\u00e3o Paulo  Ribeir\u00e3o Preto 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