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

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Abstract

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.

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Acknowledgements

This work was supported by grants from the State Key Program of the National Natural Science Foundation (81930086 and 82120108012 to BS, 82073157 and 81600487 to WT), the Science and Technology Project of Jiangsu Province (BE2018603 to BS), and the Postgraduate Innovative Research Program of Jiangsu Province (KYCX20_0047 to QH). BS is a Yangtze River scholars Distinguished Professor.

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QH, YLu, WT, RJ, and BS designed the experiments. QH, YLu, WT, RJ, WY, YLiu, MS, FW, HZ, and NW performed the experiments, provided reagents, and/or analyzed the data. QH, YLu, WT, and ZD discussed and interpreted the data. QH and BS wrote and revised the paper. BS conceived, supervised, and revised the study.

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Correspondence to Beicheng Sun.

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He, Q., Lu, Y., Tian, W. et al. TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis. Cell Mol Immunol 19, 1102–1116 (2022). https://doi.org/10.1038/s41423-022-00912-y

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  • DOI: https://doi.org/10.1038/s41423-022-00912-y

Keywords

  • Autoimmune hepatitis
  • γδ T cell
  • IL-17A
  • Immune tolerance
  • TOX

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