Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Antonio Riva; Vishal Patel; Ayako Kurioka; Hannah C Jeffery; Gavin Wright; Sarah Tarff; Debbie Shawcross; Jennifer M Ryan; Alexander Evans; Sarah Azarian; Jasmohan S Bajaj; Andrew Fagan; Vinood Patel; Kosha Mehta; Carlos Lopez; Marieta Simonova; Krum Katzarov; Tanya Hadzhiolova; Slava Pavlova; Julia A Wendon; Ye Htun Oo; Paul Klenerman; Roger Williams; Shilpa Chokshi

doi:10.1136/gutjnl-2017-314458

Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Antonio Riva, Vishal Patel, Ayako Kurioka, Hannah C Jeffery, Gavin Wright, Sarah Tarff, Debbie Shawcross, Jennifer M Ryan, Alexander Evans, Sarah Azarian, Jasmohan S Bajaj, Andrew Fagan, Vinood Patel, Kosha Mehta, Carlos Lopez, Marieta Simonova, Krum Katzarov, Tanya Hadzhiolova, Slava Pavlova, Julia A WendonYe Htun Oo, Paul Klenerman, Roger Williams, Shilpa Chokshi

Immunology and Immunotherapy

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Abstract

BACKGROUND/AIMS: Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.

METHODS/DESIGN: We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.

RESULTS: In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.

CONCLUSIONS: In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

Original language	English
Journal	Gut
Early online date	2 Nov 2017
DOIs	https://doi.org/10.1136/gutjnl-2017-314458
Publication status	E-pub ahead of print - 2 Nov 2017

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Riva, A., Patel, V., Kurioka, A., Jeffery, H. C., Wright, G., Tarff, S., Shawcross, D., Ryan, J. M., Evans, A., Azarian, S., Bajaj, J. S., Fagan, A., Patel, V., Mehta, K., Lopez, C., Simonova, M., Katzarov, K., Hadzhiolova, T., Pavlova, S., ... Chokshi, S. (2017). Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease. Gut. Advance online publication. https://doi.org/10.1136/gutjnl-2017-314458

@article{ee13f962126c48b181f47df2b4595d6d,

title = "Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease",

abstract = "BACKGROUND/AIMS: Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.METHODS/DESIGN: We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.RESULTS: In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.CONCLUSIONS: In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.",

author = "Antonio Riva and Vishal Patel and Ayako Kurioka and Jeffery, {Hannah C} and Gavin Wright and Sarah Tarff and Debbie Shawcross and Ryan, {Jennifer M} and Alexander Evans and Sarah Azarian and Bajaj, {Jasmohan S} and Andrew Fagan and Vinood Patel and Kosha Mehta and Carlos Lopez and Marieta Simonova and Krum Katzarov and Tanya Hadzhiolova and Slava Pavlova and Wendon, {Julia A} and Oo, {Ye Htun} and Paul Klenerman and Roger Williams and Shilpa Chokshi",

note = "{\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",

year = "2017",

month = nov,

day = "2",

doi = "10.1136/gutjnl-2017-314458",

language = "English",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

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Riva, A, Patel, V, Kurioka, A, Jeffery, HC, Wright, G, Tarff, S, Shawcross, D, Ryan, JM, Evans, A, Azarian, S, Bajaj, JS, Fagan, A, Patel, V, Mehta, K, Lopez, C, Simonova, M, Katzarov, K, Hadzhiolova, T, Pavlova, S, Wendon, JA, Oo, YH, Klenerman, P, Williams, R & Chokshi, S 2017, 'Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease', Gut. https://doi.org/10.1136/gutjnl-2017-314458

TY - JOUR

T1 - Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

AU - Riva, Antonio

AU - Patel, Vishal

AU - Kurioka, Ayako

AU - Jeffery, Hannah C

AU - Wright, Gavin

AU - Tarff, Sarah

AU - Shawcross, Debbie

AU - Ryan, Jennifer M

AU - Evans, Alexander

AU - Azarian, Sarah

AU - Bajaj, Jasmohan S

AU - Fagan, Andrew

AU - Patel, Vinood

AU - Mehta, Kosha

AU - Lopez, Carlos

AU - Simonova, Marieta

AU - Katzarov, Krum

AU - Hadzhiolova, Tanya

AU - Pavlova, Slava

AU - Wendon, Julia A

AU - Oo, Ye Htun

AU - Klenerman, Paul

AU - Williams, Roger

AU - Chokshi, Shilpa

PY - 2017/11/2

Y1 - 2017/11/2

N2 - BACKGROUND/AIMS: Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.METHODS/DESIGN: We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.RESULTS: In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.CONCLUSIONS: In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

AB - BACKGROUND/AIMS: Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.METHODS/DESIGN: We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.RESULTS: In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.CONCLUSIONS: In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

U2 - 10.1136/gutjnl-2017-314458

DO - 10.1136/gutjnl-2017-314458

M3 - Article

C2 - 29097439

SN - 0017-5749

JO - Gut

JF - Gut

ER -

Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

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