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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. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Surya P Pandey, Mackenzie J Bender, Alex C McPherson, Catherine M Phelps, Luzmariel Medina Sanchez, Mohit Rana, Lee Hedden, Kishan A Sangani, Li Chen, Jake H Shapira, Magdalena Siller, Chhavi Goel, Elena F Verdú, Bana Jabri, Alexander Chang, Uma R Chandran, Steven J Mullett, Stacy G Wendell, Aatur D Singhi, Jeremy S Tilstra, Joseph F Pierre, Gavin E Arteel, Reinhard Hinterleitner, Marlies Meisel. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis. Cell host & microbe. 2022 Jul 13;30(7):1003-1019.e10

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PMID: 35658976

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