Journal
MUCOSAL IMMUNOLOGY
Volume 12, Issue 2, Pages 479-490Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41385-018-0118-0
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Funding
- SSWO grants [SSWO 608, S16-23]
- Dutch Sophia Research Foundation
- Dutch Sophia Research Foundation SSWO grant [S14-17]
- Dutch Organization for Scientific research (NWO) (Innovative research incentives VIDI grant) [91710377]
- Genomics research initiative Zenith grant [93512004]
- NWO VIDI grant [91776365]
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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(+) CD8aa(+) IEL (CD4(+) CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4(+) CD8a(-) 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(+)CD8a(+) 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.
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