| First Author | Pandey SP | Year | 2022 |
| Journal | Cell Host Microbe | Volume | 30 |
| Issue | 7 | Pages | 1003-1019.e10 |
| PubMed ID | 35658976 | Mgi Jnum | J:347566 |
| Mgi Id | MGI:7316233 | Doi | 10.1016/j.chom.2022.05.006 |
| Citation | Pandey SP, et al. (2022) Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis. Cell Host Microbe 30(7):1003-1019.e10 |
| abstractText | The triggers that drive interferon-gamma (IFNgamma)-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 IFNgamma 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. |
