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 languageEnglish
Article number7090
Number of pages12
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 19 May 2015
Externally publishedYes

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

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