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While Aire's role in mTEC heterogeneity is well established, its contribution to the transcriptome-driven differentiation trajectory remains incompletely understood. Here, we employed single-cell RNA sequencing (scRNA-seq) of in vitro\u2013cultured murine mTECs to profile wild-type and heterozygous Aire-mutant (exon 6 c.735delG; partial loss-of-function) cells co-cultured with CD4+ thymocytes. In both genotypes, three conserved mTEC subpopulations were identified\u2014translating, intermediate, and antigen-presentation\u2013related. Pseudotime analysis revealed that the overall differentiation trajectory was preserved despite Aire deficiency, although with reduced transcriptional diversity, lower TRA expression, and attenuated MHC-related gene activity. Aire-mutant mTECs exhibited global transcriptional downregulation, including diminished expression of Aire partner genes involved in chromatin regulation and antigen processing. These findings indicate that Aire functions as a transcriptional amplifier and facilitator of efficient progression, enhancing the amplitude and completeness of mTEC maturation without being essential for its initiation. This study provides new insights into thymic epithelial biology and highlights the existence of Aire-independent transcriptional programs that sustain mTEC differentiation and contribute to central tolerance.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag038","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:44:00Z","timestamp":1773333840000},"source":"Crossref","is-referenced-by-count":2,"title":["Single-cell RNA-seq of in vitro\u2013cultured medullary thymic epithelial cells reveals a preserved differentiation trajectory under\n                    <i>Aire<\/i>\n                    deficiency"],"prefix":"10.1093","volume":"118","author":[{"given":"Rom\u00e1rio Sousa","family":"Mascarenhas","sequence":"first","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max Jordan","family":"Duarte","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro Paranhos","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernna H","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00edntia J\u00fania","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayara C","family":"Vieira-Machado","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Ant\u00f4nio","family":"Donadi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Clinical Immunology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-140X","authenticated-orcid":false,"given":"Geraldo Aleixo","family":"Passos","sequence":"additional","affiliation":[{"name":"Molecular Immunogenetics Group, Department of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Via Bandeirantes, 3900, Ribeir\u00e3o Preto Campus, SP 14040-900 ,","place":["Brazil"]},{"name":"Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, Ribeir\u00e3o Preto School of Dentistry, University of S\u00e3o Paulo , Via do Caf\u00e9 s\/n, Ribeir\u00e3o Preto Campus, SP 14040-904 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