Loss Of  Tet2  In T Cells Drives Translocated Pathobiont Derived Aryl Hydrocarbon Receptor Agonist-Induced Tc1 Cell Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH) is a progressive, auto-inflammatory liver disorder mediated by interferon-γ (IFNγ)-producing CD8 T cells (Tc1-cells). Here we show that the absence of hematopoietic Tet-methylcytosine-dioxygenase2 (Tet2, Tet2ΔVAV mice), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by a hepatic enrichment of aryl-hydrocarbon-receptor (AhR) ligand-producing pathobionts. We identified that blocking IFNγ reverts ongoing AIH in Tet2ΔVAV mice, and further show that the absence of Tet2 in T cells, which are required for this condition, is sufficient to drive AIH. Further, AIH-like disease only developed in liver-dysbiotic Tet2ΔVAV mice and hepatic translocation of AhR ligand-producing Lactobacillus reuteri (L.reuteri), but not non-AhR-ligand producing L.johnsonii, was sufficient to selectively trigger Tc1-cell-mediated AIH in symptom-free Tet2ΔVAV mice. Furthermore, Tet2 within CD8 T cells antagonized L.reuteri-induced Tc1-cell fate in an AhR-dependent manner in-vitro. Our study may contribute to the development of novel therapeutic avenues that alleviate human AIH.

Keywords: autoimmune hepatitis, liver microbiome, Lactobacillus reuteri, aryl hydrocarbon receptor agonist, Tc1 cells, Tet2