{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Pandey SP"],"funding":["NIDDK NIH HHS","NIAID NIH HHS","NIAAA NIH HHS","NCI NIH HHS","NIAMS NIH HHS","NIH HHS","NIGMS NIH HHS"],"pagination":["1003-1019.e10"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9841318"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["30(7)"],"pubmed_abstract":["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."],"journal":["Cell host & microbe"],"pubmed_title":["Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis."],"pmcid":["PMC9841318"],"funding_grant_id":["P30 DK120531","R01 AA030007","R01 AA028436","R01 CA253329","R21 AI163721","R21 AI163503","P30 CA047904","R01 DK130897","R21 CA259636","T32 AI089443","R01 AA021978","K08 AR075056","T32 GM007281","S10 OD023402"],"pubmed_authors":["Sanchez LM","Goel C","McPherson AC","Shapira JH","Sangani KA","Bender MJ","Arteel GE","Chen L","Jabri B","Siller M","Hedden L","Hinterleitner R","Pandey SP","Chandran UR","Wendell SG","Pierre JF","Phelps CM","Verdu EF","Chang A","Mullett SJ","Singhi AD","Meisel M","Rana M","Tilstra JS"],"additional_accession":[]},"is_claimable":false,"name":"Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jul","modification":"2026-05-28T11:30:19.006Z","creation":"2025-02-19T03:27:28.227Z"},"accession":"S-EPMC9841318","cross_references":{"pubmed":["35658976"],"doi":["10.1016/j.chom.2022.05.006"]}}