Journal
MUCOSAL IMMUNOLOGY
Volume 12, Issue 5, Pages 1201-1211Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41385-019-0194-9
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Funding
- Dutch Sophia Foundation [557, 671, S14-17]
- Erasmus University Rotterdam
- Ter Meulen Fund of the Royal Netherlands Academy of Arts and Sciences
- European Crohn's and Colitis Organization
- International Organization for the Study of Inflammatory Bowel Disease
- Netherlands Organization for Scientific Research [2013/09420/BOO]
- Division of Intramural Research, NHLBI
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Uncontrolled interferon gamma (IFN gamma)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFN gamma-secreting CD4(+) T cells. Deficiency in IL-10 signaling dramatically increased IL-1 beta release by moDCs. IL-1 beta boosted IFN gamma secretion by CD4(+) T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1 beta expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFN gamma-secreting CD4(+) T cells in humans and identifies IL-1 beta as a potential classifier for a subgroup of IBD patients.
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