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Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury

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Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury. / Hackstein, Carl-Philipp; Spitzer, Jasper; Symeonidis, Konstantinos; Horvatic, Helena; Bedke, Tanja; Steglich, Babett; Klein, Sabine; Assmus, Lisa M; Odainic, Alexandru; Szlapa, Jennifer; Kessler, Nina; Beyer, Marc; Schmithausen, Ricarda; Latz, Eicke; Flavell, Richard A; Garbi, Natalio; Kurts, Christian; Kümmerer, Beate M; Trebicka, Jonel; Roers, Axel; Huber, Samuel; Schmidt, Susanne V; Knolle, Percy A; Abdullah, Zeinab.

In: J HEPATOL, Vol. 79, No. 1, 07.2023, p. 150-166.

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

Harvard

Hackstein, C-P, Spitzer, J, Symeonidis, K, Horvatic, H, Bedke, T, Steglich, B, Klein, S, Assmus, LM, Odainic, A, Szlapa, J, Kessler, N, Beyer, M, Schmithausen, R, Latz, E, Flavell, RA, Garbi, N, Kurts, C, Kümmerer, BM, Trebicka, J, Roers, A, Huber, S, Schmidt, SV, Knolle, PA & Abdullah, Z 2023, 'Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury', J HEPATOL, vol. 79, no. 1, pp. 150-166. https://doi.org/10.1016/j.jhep.2023.02.026

APA

Hackstein, C-P., Spitzer, J., Symeonidis, K., Horvatic, H., Bedke, T., Steglich, B., Klein, S., Assmus, L. M., Odainic, A., Szlapa, J., Kessler, N., Beyer, M., Schmithausen, R., Latz, E., Flavell, R. A., Garbi, N., Kurts, C., Kümmerer, B. M., Trebicka, J., ... Abdullah, Z. (2023). Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury. J HEPATOL, 79(1), 150-166. https://doi.org/10.1016/j.jhep.2023.02.026

Vancouver

Hackstein C-P, Spitzer J, Symeonidis K, Horvatic H, Bedke T, Steglich B et al. Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury. J HEPATOL. 2023 Jul;79(1):150-166. https://doi.org/10.1016/j.jhep.2023.02.026

Bibtex

@article{e2295bc764e54afba938d2a333bbf171,
title = "Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury",
abstract = "BACKGROUND & AIMS: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD.METHODS: We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and SARS-CoV-2 vaccinations in patients with CLD and healthy individuals in a proof-of-concept clinical study.RESULTS: We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination and viral infection in mice, subsequently leading to persistent infection. We observed a similarly defective T-cell response to vaccination in patients with cirrhosis. Innate sensing of translocated gut microbiota induced IFN-I signaling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signaling in antigen-specific T cells rendered them dysfunctional. Antibiotic treatment and inhibition of IFNAR or IL-10Ra restored antiviral immunity without detectable immune pathology in mice. Notably, IL-10Ra blockade restored the functional phenotype of T cells from vaccinated patients with cirrhosis.CONCLUSION: Innate sensing of translocated microbiota induces IFN-/IL-10 expression, which drives the loss of systemic T-cell immunity during prolonged liver injury.IMPACT AND IMPLICATIONS: Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hyporesponsiveness. Using different preclinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signaling leading to myeloid cell-induced IL-10 expression, and IL-10 signaling in antigen-specific T cells. Given the absence of immune pathology after interference with IL-10R, our study highlights a potential novel target to reconstitute T-cell immunity in patients with CLD that can be explored in future clinical studies.",
keywords = "Mice, Animals, Interleukin-10, COVID-19, SARS-CoV-2, Interferon Type I, Mice, Transgenic, Liver Cirrhosis, Mice, Inbred C57BL",
author = "Carl-Philipp Hackstein and Jasper Spitzer and Konstantinos Symeonidis and Helena Horvatic and Tanja Bedke and Babett Steglich and Sabine Klein and Assmus, {Lisa M} and Alexandru Odainic and Jennifer Szlapa and Nina Kessler and Marc Beyer and Ricarda Schmithausen and Eicke Latz and Flavell, {Richard A} and Natalio Garbi and Christian Kurts and K{\"u}mmerer, {Beate M} and Jonel Trebicka and Axel Roers and Samuel Huber and Schmidt, {Susanne V} and Knolle, {Percy A} and Zeinab Abdullah",
note = "Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier B.V. All rights reserved.",
year = "2023",
month = jul,
doi = "10.1016/j.jhep.2023.02.026",
language = "English",
volume = "79",
pages = "150--166",
journal = "J HEPATOL",
issn = "0168-8278",
publisher = "Elsevier",
number = "1",

}

RIS

TY - JOUR

T1 - Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury

AU - Hackstein, Carl-Philipp

AU - Spitzer, Jasper

AU - Symeonidis, Konstantinos

AU - Horvatic, Helena

AU - Bedke, Tanja

AU - Steglich, Babett

AU - Klein, Sabine

AU - Assmus, Lisa M

AU - Odainic, Alexandru

AU - Szlapa, Jennifer

AU - Kessler, Nina

AU - Beyer, Marc

AU - Schmithausen, Ricarda

AU - Latz, Eicke

AU - Flavell, Richard A

AU - Garbi, Natalio

AU - Kurts, Christian

AU - Kümmerer, Beate M

AU - Trebicka, Jonel

AU - Roers, Axel

AU - Huber, Samuel

AU - Schmidt, Susanne V

AU - Knolle, Percy A

AU - Abdullah, Zeinab

N1 - Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2023/7

Y1 - 2023/7

N2 - BACKGROUND & AIMS: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD.METHODS: We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and SARS-CoV-2 vaccinations in patients with CLD and healthy individuals in a proof-of-concept clinical study.RESULTS: We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination and viral infection in mice, subsequently leading to persistent infection. We observed a similarly defective T-cell response to vaccination in patients with cirrhosis. Innate sensing of translocated gut microbiota induced IFN-I signaling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signaling in antigen-specific T cells rendered them dysfunctional. Antibiotic treatment and inhibition of IFNAR or IL-10Ra restored antiviral immunity without detectable immune pathology in mice. Notably, IL-10Ra blockade restored the functional phenotype of T cells from vaccinated patients with cirrhosis.CONCLUSION: Innate sensing of translocated microbiota induces IFN-/IL-10 expression, which drives the loss of systemic T-cell immunity during prolonged liver injury.IMPACT AND IMPLICATIONS: Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hyporesponsiveness. Using different preclinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signaling leading to myeloid cell-induced IL-10 expression, and IL-10 signaling in antigen-specific T cells. Given the absence of immune pathology after interference with IL-10R, our study highlights a potential novel target to reconstitute T-cell immunity in patients with CLD that can be explored in future clinical studies.

AB - BACKGROUND & AIMS: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD.METHODS: We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and SARS-CoV-2 vaccinations in patients with CLD and healthy individuals in a proof-of-concept clinical study.RESULTS: We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination and viral infection in mice, subsequently leading to persistent infection. We observed a similarly defective T-cell response to vaccination in patients with cirrhosis. Innate sensing of translocated gut microbiota induced IFN-I signaling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signaling in antigen-specific T cells rendered them dysfunctional. Antibiotic treatment and inhibition of IFNAR or IL-10Ra restored antiviral immunity without detectable immune pathology in mice. Notably, IL-10Ra blockade restored the functional phenotype of T cells from vaccinated patients with cirrhosis.CONCLUSION: Innate sensing of translocated microbiota induces IFN-/IL-10 expression, which drives the loss of systemic T-cell immunity during prolonged liver injury.IMPACT AND IMPLICATIONS: Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hyporesponsiveness. Using different preclinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signaling leading to myeloid cell-induced IL-10 expression, and IL-10 signaling in antigen-specific T cells. Given the absence of immune pathology after interference with IL-10R, our study highlights a potential novel target to reconstitute T-cell immunity in patients with CLD that can be explored in future clinical studies.

KW - Mice

KW - Animals

KW - Interleukin-10

KW - COVID-19

KW - SARS-CoV-2

KW - Interferon Type I

KW - Mice, Transgenic

KW - Liver Cirrhosis

KW - Mice, Inbred C57BL

U2 - 10.1016/j.jhep.2023.02.026

DO - 10.1016/j.jhep.2023.02.026

M3 - SCORING: Journal article

C2 - 36870611

VL - 79

SP - 150

EP - 166

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 1

ER -