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

• Published in: Mucosal immunology Vol. 12; no. 2; pp. 479 - 490
• Main Authors: Costes, L M M, Lindenbergh-Kortleve, D J, van Berkel, L A, Veenbergen, S, Raatgeep, H R C, Simons-Oosterhuis, Y, van Haaften, D H, Karrich, J J, Escher, J C, Groeneweg, M, Clausen, B E, Cupedo, T, Samsom, J N
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2019
• Subjects: Animals; Atrophy; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Celiac disease; Celiac Disease - immunology; Cell Death; Cell Differentiation; Cell Movement; Child; Cytotoxicity; Cytotoxicity, Immunologic; Epithelial cells; Gluten; Glutens - immunology; Granzyme B; Granzymes - metabolism; Homeostasis; Humans; Hyperplasia; Immune Tolerance; Immunological tolerance; Infiltration; Inflammation; Interleukin 1; Interleukin 10; Interleukin 21; Interleukin-10 - genetics; Interleukin-10 - metabolism; Intestinal Mucosa - immunology; Intraepithelial Lymphocytes - immunology; Lymphocyte Activation; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Transgenic; Signal Transduction; Small intestine; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/s41385-018-0118-0

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.