TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis.
Cell Mol Immunol
; 19(10): 1102-1116, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35986136
ABSTRACT
The specification of the αß/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 αß/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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Base de dados:
MEDLINE
Assunto principal:
Hepatite Autoimune
/
Interleucina-17
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article