Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis

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. TilstraJoseph F. Pierre, Gavin E. Arteel, Reinhard Hinterleitner, Marlies Meisel

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)1003-1019.e10
JournalCell Host and Microbe
Volume30
Issue number7
DOIs
StatePublished - 13 Jul 2022
Externally publishedYes

Keywords

  • Lactobacillus reuteri
  • Tc1 cells
  • Tet2
  • aryl hydrocarbon receptor agonist
  • autoimmune hepatitis
  • liver microbiome

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