Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis

The triggers that drive interferon-gamma (IFN gamma)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFN gamma and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.

Automated summary

This study reveals that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2) contributes to the development of autoimmune hepatitis (AIH). AIH is associated with interferon-gamma and aryl hydrocarbon receptor (AhR) signaling pathways, as well as the presence of AhR ligand-producing pathobionts in the liver. Furthermore, the study demonstrates that the AhR ligand indole-3aldehyde (I3A) released by Lactobacillus reuteri can trigger AIH-like pathology.