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Intraepithelial lymphocytes in celiac disease immunopathology

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Abstract

Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.

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Acknowledgments

We thank CD patients and their family members as well as the University of Chicago Celiac Disease Center for supporting our research. We thank B. Sally for critical reading of the manuscript.

This work was supported by the Digestive Diseases Research Core Center at the University of Chicago (DK42086), RO1 DK67180, and DK058727 (for B.J.) and a fellowship of the Italian Society for Pediatric Gastroenterology, Hepatology, and Nutrition (SIGENP) (for V.D.).

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Authors and Affiliations

  1. Sainte-Justine Hospital Research Centre, Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1C5, Canada

    Valérie Abadie

  2. Department of Pediatrics, University of Chicago, Chicago, IL, 60637, USA

    Valentina Discepolo & Bana Jabri

  3. European Laboratory for the Investigation of Food Induced Diseases (ELFID), Department of Pediatrics, University of Naples Federico II, Naples, Italy

    Valentina Discepolo

  4. Department of Medicine and Department of Pathology, University of Chicago, Chicago, IL, 60637, USA

    Bana Jabri

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  1. Valérie Abadie
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  2. Valentina Discepolo
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  3. Bana Jabri
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Correspondence to Valérie Abadie or Bana Jabri.

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This article is published as part of the Special Issue on Celiac Disease [34:5].

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Abadie, V., Discepolo, V. & Jabri, B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol 34, 551–566 (2012). https://doi.org/10.1007/s00281-012-0316-x

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