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

Veenbergen, S;Li, P;Raatgeep, HC;Lindenbergh-Kortleve, DJ;Simons-Oosterhuis, Y;Farrel, A;Costes, LMM;Joosse, ME;van Berkel, LA;de Ruiter, LF;van Leeuwen, MA;Winter, D;Holland, SM;Freeman, AF;Wakabayashi, Y;Zhu, J;de Ridder, L;Driessen, GJ;Escher, JC;Leona

Uncontrolled interferon (IFN)-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-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1 release by moDCs. IL-1 boosted IFN 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 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-secreting CD4+ T cells in humans and identifies IL-1 as a potential classifier for a subgroup of IBD patients.