biostudies-literatureHe QNational Natural Science Foundation of Chinathe Postgraduate Innovative Research Program of Jiangsu Province1102-1116https://www.ebi.ac.uk/biostudies/studies/S-EPMC9508111biostudies-literatureUnknown19(10)The specification of the αβ/γδ lineage and the maturation of medullary thymic epithelial cells (mTECs) coordinate central tolerance to self-antigens. However, the mechanisms underlying this biological process remain poorly clarified. Here, we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation, promoted thymic IL-17A-producing γδ T-cell (Tγδ17) lineage commitment, and led to the development of fatal autoimmune hepatitis (AIH) via different mechanisms. Transfer of γδ T cells from TOX-deficient mice reproduced AIH. TOX interacted with and stabilized the TCF1 protein to maintain the balance of γδ T-cell development in thymic progenitors, and overexpression of TCF1 normalized αβ/γδ lineage specification and activation. In addition, TOX expression was downreCellular & molecular immunologyTOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis.PMC950811182120108012 to BSLiu YSun MTian WWu NLu YSun BZhang HDong ZJiang RYu WWang FHe QfalseTOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis.The specification of the αβ/γδ lineage and the maturation of medullary thymic epithelial cells (mTECs) coordinate central tolerance to self-antigens. However, the mechanisms underlying this biological process remain poorly clarified. Here, we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation, promoted thymic IL-17A-producing γδ T-cell (Tγδ17) lineage commitment, and led to the development of fatal autoimmune hepatitis (AIH) via different mechanisms. Transfer of γδ T cells from TOX-deficient mice reproduced AIH. TOX interacted with and stabilized the TCF1 protein to maintain the balance of γδ T-cell development in thymic progenitors, and overexpression of TCF1 normalized αβ/γδ lineage specification and activation. In addition, TOX expression was downre2022-01-01T00:00:00Z2022 Oct2026-05-28T02:02:21.161Z2025-04-05T15:24:37.234ZS-EPMC95081113598613610.1038/s41423-022-00912-y