biostudies-literaturePandey SPNIDDK NIH HHSNIAID NIH HHSNIAAA NIH HHSNCI NIH HHSNIAMS NIH HHSNIH HHSNIGMS NIH HHS1003-1019.e10https://www.ebi.ac.uk/biostudies/studies/S-EPMC9841318biostudies-literatureUnknown30(7)The triggers that drive interferon-γ (IFNγ)-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 IFNγ 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-3-aldehyde (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.Cell host & microbeTet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.PMC9841318P30 DK120531R01 AA030007R01 AA028436R01 CA253329R21 AI163721R21 AI163503P30 CA047904R01 DK130897R21 CA259636T32 AI089443R01 AA021978K08 AR075056T32 GM007281S10 OD023402Sanchez LMGoel CMcPherson ACShapira JHSangani KABender MJArteel GEChen LJabri BSiller MHedden LHinterleitner RPandey SPChandran URWendell SGPierre JFPhelps CMVerdu EFChang AMullett SJSinghi ADMeisel MRana MTilstra JSfalseTet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.The triggers that drive interferon-γ (IFNγ)-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 IFNγ 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-3-aldehyde (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.2022-01-01T00:00:00Z2022 Jul2026-05-28T11:30:19.006Z2025-02-19T03:27:28.227ZS-EPMC98413183565897610.1016/j.chom.2022.05.006