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Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells

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Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells. / Burghardt, Sven; Erhardt, Annette; Claass, Benjamin; Huber, Samuel; Adler, Guido; Jacobs, Thomas; Chalaris, Athena; Schmidt-Arras, Dirk; Rose-John, Stefan; Karimi, Khalil; Tiegs, Gisa.

In: J IMMUNOL, Vol. 191, No. 11, 01.12.2013, p. 5574-82.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Burghardt, S, Erhardt, A, Claass, B, Huber, S, Adler, G, Jacobs, T, Chalaris, A, Schmidt-Arras, D, Rose-John, S, Karimi, K & Tiegs, G 2013, 'Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells', J IMMUNOL, vol. 191, no. 11, pp. 5574-82. https://doi.org/10.4049/jimmunol.1300826

APA

Burghardt, S., Erhardt, A., Claass, B., Huber, S., Adler, G., Jacobs, T., Chalaris, A., Schmidt-Arras, D., Rose-John, S., Karimi, K., & Tiegs, G. (2013). Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells. J IMMUNOL, 191(11), 5574-82. https://doi.org/10.4049/jimmunol.1300826

Vancouver

Burghardt S, Erhardt A, Claass B, Huber S, Adler G, Jacobs T et al. Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells. J IMMUNOL. 2013 Dec 1;191(11):5574-82. https://doi.org/10.4049/jimmunol.1300826

Bibtex

@article{b02d69e257e249879e2168d28cf12701,
title = "Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells",
abstract = "The {"}liver tolerance effect{"} has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A-pretreated mice, induced a regulatory phenotype in naive CD4(+) T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10-producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γ-secretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A-pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4(+) T cells. However, HCs from Con A-pretreated IFN regulatory factor 1(-/-) mice, which cannot respond to IFN-γ, as well as those from IFN-γ(-/-) mice failed to augment IL-10 production by CD4(+) T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.",
keywords = "Animals, Calcium-Binding Proteins, Cells, Cultured, Disintegrins, Gene Expression Regulation, Hepatitis, Hepatocytes, Immune Tolerance, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factor-1, Interferon-gamma, Interleukin-10, Liver, Lymphocyte Activation, Male, Matrix Metalloproteinase 17, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Notch, Signal Transduction, T-Lymphocytes, Regulatory, Th1 Cells",
author = "Sven Burghardt and Annette Erhardt and Benjamin Claass and Samuel Huber and Guido Adler and Thomas Jacobs and Athena Chalaris and Dirk Schmidt-Arras and Stefan Rose-John and Khalil Karimi and Gisa Tiegs",
year = "2013",
month = dec,
day = "1",
doi = "10.4049/jimmunol.1300826",
language = "English",
volume = "191",
pages = "5574--82",
journal = "J IMMUNOL",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

RIS

TY - JOUR

T1 - Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells

AU - Burghardt, Sven

AU - Erhardt, Annette

AU - Claass, Benjamin

AU - Huber, Samuel

AU - Adler, Guido

AU - Jacobs, Thomas

AU - Chalaris, Athena

AU - Schmidt-Arras, Dirk

AU - Rose-John, Stefan

AU - Karimi, Khalil

AU - Tiegs, Gisa

PY - 2013/12/1

Y1 - 2013/12/1

N2 - The "liver tolerance effect" has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A-pretreated mice, induced a regulatory phenotype in naive CD4(+) T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10-producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γ-secretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A-pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4(+) T cells. However, HCs from Con A-pretreated IFN regulatory factor 1(-/-) mice, which cannot respond to IFN-γ, as well as those from IFN-γ(-/-) mice failed to augment IL-10 production by CD4(+) T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.

AB - The "liver tolerance effect" has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A-pretreated mice, induced a regulatory phenotype in naive CD4(+) T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10-producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γ-secretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A-pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4(+) T cells. However, HCs from Con A-pretreated IFN regulatory factor 1(-/-) mice, which cannot respond to IFN-γ, as well as those from IFN-γ(-/-) mice failed to augment IL-10 production by CD4(+) T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.

KW - Animals

KW - Calcium-Binding Proteins

KW - Cells, Cultured

KW - Disintegrins

KW - Gene Expression Regulation

KW - Hepatitis

KW - Hepatocytes

KW - Immune Tolerance

KW - Intercellular Signaling Peptides and Proteins

KW - Interferon Regulatory Factor-1

KW - Interferon-gamma

KW - Interleukin-10

KW - Liver

KW - Lymphocyte Activation

KW - Male

KW - Matrix Metalloproteinase 17

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Receptors, Notch

KW - Signal Transduction

KW - T-Lymphocytes, Regulatory

KW - Th1 Cells

U2 - 10.4049/jimmunol.1300826

DO - 10.4049/jimmunol.1300826

M3 - SCORING: Journal article

C2 - 24140644

VL - 191

SP - 5574

EP - 5582

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 11

ER -