Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance

Mahima Swamy; Lucie Abeler-Dörner; James Chettle; Tanel Mahlakõiv; Delphine Goubau; Probir Chakravarty; George Ramsay; Caetano Reis e Sousa; Peter Staeheli; Barbara A Blacklaws; Jonathan L Heeney; Adrian C Hayday

doi:10.1038/ncomms8090

Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance

Mahima Swamy, Lucie Abeler-Dörner, James Chettle, Tanel Mahlakõiv, Delphine Goubau, Probir Chakravarty, George Ramsay, Caetano Reis e Sousa, Peter Staeheli, Barbara A Blacklaws, Jonathan L Heeney, Adrian C Hayday

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Abstract

Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.

Original language	English
Article number	7090
Number of pages	12
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8090
Publication status	Published - 19 May 2015
Externally published	Yes

Bibliographical note

Support was provided by the Wellcome Trust (A.C.H., J.L.H., G.R) and Cancer Research UK (A.C.H.), Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust (L.A.-D.; A.C.H.); Marie Curie and EMBO fellowships (M.S.). We thank Professor D. Cantrell for generous support of M.S.; Dr D. Kaiserlien (Lyon) for the gift of MODE-K cells; Dr B. Spencer-Dene for histological stainings; Dr P. East for contributing to microarray data analysis, and our many colleagues for useful discussions and criticisms, particularly Dr V. Hornung. We acknowledge the staffs of the flow cytometry and animal care facilities of the Francis Crick Institute, Lincoln's Inn Fields Laboratories, London, UK, King’s College London, and the Universities of Freiburg, Cambridge, and Dundee.

Keywords

Animals
Caliciviridae Infections
Cytokines
Epithelial Cells
Female
Gastroenteritis
Immunity, Innate
Interferon-alpha
Interferon-gamma
Interferons
Intestine, Small
Lymphocyte Activation
Lymphocytes
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Norovirus
T-Lymphocytes
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance
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Final published version, 1.14 MBLicence: CC BY

George Ramsay
- School of Medicine, Medical Sciences & Nutrition, Health Services Research Unit (HSRU) - Senior Clinical Lecturer
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cancer Centre
Person: Clinical Academic

Cite this

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title = "Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance",

abstract = "Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium. ",

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author = "Mahima Swamy and Lucie Abeler-D{\"o}rner and James Chettle and Tanel Mahlak{\~o}iv and Delphine Goubau and Probir Chakravarty and George Ramsay and {Reis e Sousa}, Caetano and Peter Staeheli and Blacklaws, {Barbara A} and Heeney, {Jonathan L} and Hayday, {Adrian C}",

note = "Support was provided by the Wellcome Trust (A.C.H., J.L.H., G.R) and Cancer Research UK (A.C.H.), Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust (L.A.-D.; A.C.H.); Marie Curie and EMBO fellowships (M.S.). We thank Professor D. Cantrell for generous support of M.S.; Dr D. Kaiserlien (Lyon) for the gift of MODE-K cells; Dr B. Spencer-Dene for histological stainings; Dr P. East for contributing to microarray data analysis, and our many colleagues for useful discussions and criticisms, particularly Dr V. Hornung. We acknowledge the staffs of the flow cytometry and animal care facilities of the Francis Crick Institute, Lincoln's Inn Fields Laboratories, London, UK, King{\textquoteright}s College London, and the Universities of Freiburg, Cambridge, and Dundee.",

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language = "English",

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journal = "Nature Communications",

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TY - JOUR

T1 - Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance

AU - Swamy, Mahima

AU - Abeler-Dörner, Lucie

AU - Chettle, James

AU - Mahlakõiv, Tanel

AU - Goubau, Delphine

AU - Chakravarty, Probir

AU - Ramsay, George

AU - Reis e Sousa, Caetano

AU - Staeheli, Peter

AU - Blacklaws, Barbara A

AU - Heeney, Jonathan L

AU - Hayday, Adrian C

N1 - Support was provided by the Wellcome Trust (A.C.H., J.L.H., G.R) and Cancer Research UK (A.C.H.), Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust (L.A.-D.; A.C.H.); Marie Curie and EMBO fellowships (M.S.). We thank Professor D. Cantrell for generous support of M.S.; Dr D. Kaiserlien (Lyon) for the gift of MODE-K cells; Dr B. Spencer-Dene for histological stainings; Dr P. East for contributing to microarray data analysis, and our many colleagues for useful discussions and criticisms, particularly Dr V. Hornung. We acknowledge the staffs of the flow cytometry and animal care facilities of the Francis Crick Institute, Lincoln's Inn Fields Laboratories, London, UK, King’s College London, and the Universities of Freiburg, Cambridge, and Dundee.

PY - 2015/5/19

Y1 - 2015/5/19

N2 - Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.

AB - Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.

KW - Animals

KW - Caliciviridae Infections

KW - Cytokines

KW - Epithelial Cells

KW - Female

KW - Gastroenteritis

KW - Immunity, Innate

KW - Interferon-alpha

KW - Interferon-gamma

KW - Interferons

KW - Intestine, Small

KW - Lymphocyte Activation

KW - Lymphocytes

KW - Macrophages

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Norovirus

KW - T-Lymphocytes

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ncomms8090

DO - 10.1038/ncomms8090

M3 - Article

C2 - 25987506

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7090

ER -

Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance

Abstract

Bibliographical note

Keywords

UN SDGs

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George Ramsay

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