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. Tilstra; Joseph F. Pierre; Gavin E. Arteel; Reinhard Hinterleitner; Marlies Meisel

doi:10.1016/j.chom.2022.05.006

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 journal › Article › peer-review

35 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 language	English
Pages (from-to)	1003-1019.e10
Journal	Cell Host and Microbe
Volume	30
Issue number	7
DOIs	https://doi.org/10.1016/j.chom.2022.05.006
State	Published - 13 Jul 2022
Externally published	Yes

Keywords

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

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10.1016/j.chom.2022.05.006

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Pandey, S. P., Bender, M. J., McPherson, A. C., Phelps, C. M., Sanchez, L. M., Rana, M., Hedden, L., Sangani, K. A., Chen, L., Shapira, J. H., Siller, M., Goel, C., Verdú, E. F., Jabri, B., Chang, A., Chandran, U. R., Mullett, S. J., Wendell, S. G., Singhi, A. D., ... Meisel, M. (2022). Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis. Cell Host and Microbe, 30(7), 1003-1019.e10. https://doi.org/10.1016/j.chom.2022.05.006

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title = "Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis",

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.",

keywords = "Lactobacillus reuteri, Tc1 cells, Tet2, aryl hydrocarbon receptor agonist, autoimmune hepatitis, liver microbiome",

author = "Pandey, {Surya P.} and Bender, {Mackenzie J.} and McPherson, {Alex C.} and Phelps, {Catherine M.} and Sanchez, {Luzmariel Medina} and Mohit Rana and Lee Hedden and Sangani, {Kishan A.} and Li Chen and Shapira, {Jake H.} and Magdalena Siller and Chhavi Goel and Verd{\'u}, {Elena F.} and Bana Jabri and Alexander Chang and Chandran, {Uma R.} and Mullett, {Steven J.} and Wendell, {Stacy G.} and Singhi, {Aatur D.} and Tilstra, {Jeremy S.} and Pierre, {Joseph F.} and Arteel, {Gavin E.} and Reinhard Hinterleitner and Marlies Meisel",

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year = "2022",

month = jul,

day = "13",

doi = "10.1016/j.chom.2022.05.006",

language = "English",

volume = "30",

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Pandey, SP, Bender, MJ, McPherson, AC, Phelps, CM, Sanchez, LM, Rana, M, Hedden, L, Sangani, KA, Chen, L, Shapira, JH, Siller, M, Goel, C, Verdú, EF, Jabri, B, Chang, A, Chandran, UR, Mullett, SJ, Wendell, SG, Singhi, AD, Tilstra, JS, Pierre, JF, Arteel, GE, Hinterleitner, R & Meisel, M 2022, 'Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis', Cell Host and Microbe, vol. 30, no. 7, pp. 1003-1019.e10. https://doi.org/10.1016/j.chom.2022.05.006

TY - JOUR

T1 - Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis

AU - Pandey, Surya P.

AU - Bender, Mackenzie J.

AU - McPherson, Alex C.

AU - Phelps, Catherine M.

AU - Sanchez, Luzmariel Medina

AU - Rana, Mohit

AU - Hedden, Lee

AU - Sangani, Kishan A.

AU - Chen, Li

AU - Shapira, Jake H.

AU - Siller, Magdalena

AU - Goel, Chhavi

AU - Verdú, Elena F.

AU - Jabri, Bana

AU - Chang, Alexander

AU - Chandran, Uma R.

AU - Mullett, Steven J.

AU - Wendell, Stacy G.

AU - Singhi, Aatur D.

AU - Tilstra, Jeremy S.

AU - Pierre, Joseph F.

AU - Arteel, Gavin E.

AU - Hinterleitner, Reinhard

AU - Meisel, Marlies

PY - 2022/7/13

Y1 - 2022/7/13

N2 - 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.

AB - 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.

KW - Lactobacillus reuteri

KW - Tc1 cells

KW - Tet2

KW - aryl hydrocarbon receptor agonist

KW - autoimmune hepatitis

KW - liver microbiome

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U2 - 10.1016/j.chom.2022.05.006

DO - 10.1016/j.chom.2022.05.006

M3 - Article

C2 - 35658976

AN - SCOPUS:85133868597

SN - 1931-3128

VL - 30

SP - 1003-1019.e10

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 7

ER -

Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis

Abstract

Keywords

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