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IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4+T cells: relevance to inflammatory bowel disease

Authors :
Veenbergen, S.
Li, P.
Raatgeep, H.C.
Lindenbergh-Kortleve, D.J.
Simons-Oosterhuis, Y.
Farrel, A.
Costes, L.M.M.
Joosse, M.E.
van Berkel, L.A.
de Ruiter, L.F.
van Leeuwen, M.A.
Winter, D.
Holland, S.M.
Freeman, A.F.
Wakabayashi, Y.
Zhu, J.
de Ridder, L.
Driessen, G.J.
Escher, J.C.
Leonard, W.J.
Samsom, J.N.
Source :
Mucosal immunology; September 2019, Vol. 12 Issue: 5 p1201-1211, 11p
Publication Year :
2019

Abstract

Uncontrolled interferon γ (IFNγ)-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 IL10RAdeficiency or STAT3mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ 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-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RAexpression 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 IFNγ-secreting CD4+T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.

Details

Language :
English
ISSN :
19330219 and 19353456
Volume :
12
Issue :
5
Database :
Supplemental Index
Journal :
Mucosal immunology
Publication Type :
Periodical
Accession number :
ejs62071664
Full Text :
https://doi.org/10.1038/s41385-019-0194-9