TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis

Cell Mol Immunol. 2022 Oct;19(10):1102-1116. doi: 10.1038/s41423-022-00912-y. Epub 2022 Aug 19.


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 downregulated in γδ T cells from AIH patients and was inversely correlated with the AIH diagnostic score. Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.

Keywords: Autoimmune hepatitis; IL-17A; Immune tolerance; TOX; γδ T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / metabolism
  • Hepatitis, Autoimmune*
  • Interleukin-17* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, gamma-delta
  • T-Lymphocytes
  • Thymus Gland


  • Autoantigens
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta