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This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females. To investigate this, we analyzed sex-specific differences in TCR generation and selection. We examined TCR repertoires in double-positive thymocytes and single-positive thymic cells, including CD8\n                    <jats:sup>+<\/jats:sup>\n                    and CD4\n                    <jats:sup>+<\/jats:sup>\n                    effector T cells and regulatory T cells (Tregs), derived from male and female organ donors. Minimal sex-based differences were observed in V and J gene usage, and there were no notable differences in TCR repertoire diversity, complementarity-determining region 3 (CDR3) length, amino acid composition, or network structure. No TCR sequences were exclusive to either sex. However, female effector T cells exhibited a significantly higher prevalence of TCRs specific to self-antigens implicated in autoimmunity compared to males, while female Tregs showed a reduced frequency of such TCRs. These differences were not observed for TCRs targeting self-antigens unrelated to autoimmunity or antigens associated with cancer or viruses. Our findings identify a sex-specific imbalance in thymic selection of TCRs with autoimmunity-associated specificities, providing mechanistic insight into the increased susceptibility of women to autoimmune diseases.\n                  <\/jats:p>","DOI":"10.7554\/elife.109041","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T14:30:15Z","timestamp":1765290615000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.109041","source":"Crossref","is-referenced-by-count":0,"title":["Thymic selection of the T cell receptor repertoire is biased toward autoimmunity in females"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8759-1208","authenticated-orcid":true,"given":"H\u00e9l\u00e8ne","family":"Vantomme","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02en5vm52","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology, Immunopathology, Immunotherapy i3 Lab, INSERM UMRS-959, Sorbonne 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