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Mucosal Immunol. 2019 Mar;12(2):479-490. doi: 10.1038/s41385-018-0118-0. Epub 2018 Dec 12.

IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

Author information

1
Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands.
2
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands.
3
Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
4
Department of Pediatrics, Maasstad Hospital, Rotterdam, 3079 DZ, The Netherlands.
5
Institute for Molecular Medicine, University Medical Center of Johannes Gutenberg University, Mainz, 55131, Germany.
6
Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands. j.samsom@erasmusmc.nl.

Abstract

Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

PMID:
30542112
DOI:
10.1038/s41385-018-0118-0
[Indexed for MEDLINE]

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