Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.
Lactobacillus reuteri
Tc1 cells
Tet2
aryl hydrocarbon receptor agonist
autoimmune hepatitis
liver microbiome
Journal
Cell host & microbe
ISSN: 1934-6069
Titre abrégé: Cell Host Microbe
Pays: United States
ID NLM: 101302316
Informations de publication
Date de publication:
13 07 2022
13 07 2022
Historique:
received:
11
10
2021
revised:
04
03
2022
accepted:
09
05
2022
pubmed:
7
6
2022
medline:
19
7
2022
entrez:
6
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35658976
pii: S1931-3128(22)00266-9
doi: 10.1016/j.chom.2022.05.006
pmc: PMC9841318
mid: NIHMS1858316
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Ligands
0
Interferon-gamma
82115-62-6
Dioxygenases
EC 1.13.11.-
Tet2 protein, mouse
EC 1.13.11.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1003-1019.e10Subventions
Organisme : NIAID NIH HHS
ID : R21 AI163721
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA253329
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA259636
Pays : United States
Organisme : NIH HHS
ID : S10 OD023402
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007281
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI089443
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130897
Pays : United States
Organisme : NIAMS NIH HHS
ID : K08 AR075056
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA021978
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI163503
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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