OC.12.4 INNATE LYMPHOID CELLS ARE INCREASED IN CELIAC DISEASE INTESTINAL MUCOSA AND HAVE A PATHOGENIC ROLE IN A MOUSE MODEL OF SMALL INTESTINE ATROPHY

Abstract

Background and aim: Innate lymphoid cells (ILCs) are an emerging family of innate hematopoietic cells producing inflammatory cytokines and involved in the pathogenesis of several immune-mediated diseases. The aim of our study was to characterize the tissue distribution of ILCs in celiac disease (CD) and analyze their role in gut tissue damage. Materials and methods: ILC subpopulations were analyzed in lamina propria mononuclear cells (LPMCs), isolated from duodenal biopsies of patients with active CD, patients with inactive CD on a gluten-free diet and healthy controls (HC) and jejunal specimens of patients undergoing gastro-intestinal bypass by flow cytometry. Cytokines, transcription factors and receptors for interleukin (IL)-15, interferon (IFN)-alpha and Toll-like receptors (TLR) were assessed in ILCs either freshly isolated or following incubation of control LPMC with IL-15, IFNalpha and poly I:C, a TLR agonist, by flow cytometry. The role of ILCs in gut tissue damage was evaluated in a mouse model of poly I:C-driven small intestine atrophy. Results: The percentage of total ILCs did not differ between CD (both active and inactive) patients and HC. However, the fractions of ILCs type 1 expressing T-bet and ILCs type 3 expressing ROR-(g)t were significantly increased in active CD compared to controls, while there was no difference in term of ILCs type 2 among groups. ILCs expressed TLR3, IL-15R, little TLR2 but not IFN-alphaR and TLR4. IL-15 and poly I:C, but not IFN-alpha increased IFNgamma expression in ILCs. In vivo in mice, depletion of ILCs significantly reduced TLR3driven small intestinal damage. Conclusions: Active CD is characterized by preferential accumulation of type 1 and type 3 ILC subpopulations and these cells respond to IL-15, a cytokine over-produced in CD, by enhancing IFN-gamma production. The demonstration that ILCs express TLR3, are functionally able to respond to poly I:C with increased synthesis of inflammatory cytokines, and contribute to TLR3-driven small intestinal atrophy delineates a novel mechanism underlying the CD-associated tissue damage.