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We previously demonstrated that dnTGF\u03b2RII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)\u2010like disease. We hypothesized that by introducing the <jats:italic>Aire<\/jats:italic> gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGF\u03b2RII Aire<jats:sup>\u2212\/\u2212<\/jats:sup> mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA\u2010seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGF\u03b2RII Aire<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8<jats:sup>+<\/jats:sup> T cell infiltrates. Depleting CD8<jats:sup>+<\/jats:sup> T cells using an anti\u2010CD8\u03b1 antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA\u2010seq data indicated the clonal expansion of hepatic CD8<jats:sup>+<\/jats:sup> T cells. In conclusion, these mice developed an autoreactive CD8<jats:sup>+<\/jats:sup> T\u2010cell\u2010mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH\u2010PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. \u00a9 2023 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6077","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T09:28:06Z","timestamp":1677576486000},"page":"222-234","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spontaneous development of an autoimmune hepatitis \u2013 primary biliary cholangitis overlap syndrome in <scp>dnTGF\u03b2RII<\/scp> Aire<sup>\u2212\/\u2212<\/sup> mice"],"prefix":"10.1002","volume":"260","author":[{"given":"Jie","family":"Long","sequence":"first","affiliation":[{"name":"Guangdong 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