E. Mann1, J. Landy2, D. Bernardo1, H. Omar Al-Hassi1, S. Peake2, R. Man2, G. Han Lee2, N. Yassin2, S. Knight1, A. Hart2, 1Imperial College London, United Kingdom, 2St. Mark's Hospital, United Kingdom
Dendritic cells (DC) drive T-cell responses, essential in ulcerative colitis (UC) pathogenesis. In the healthy gut, DC are central to maintaining immune homeostasis. The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates intestinal inflammation; activation of the AhR pathway in mice ameliorates colitis but there is no data available regarding gut DC expression of AhR in any species. We aimed to identify dysregulated functions of human gut DC in UC, to determine whether human gut DC express AhR and to identify effects of the specific synthetic AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) on DC.
Human gut DC from healthy controls and active UC patients were isolated from colonic biopsies, analysed for AhR expression or conditioned for 90 minutes +/− FICZ. DC were co-cultured with T-cells in a mixed leucocyte reaction. Stimulated T-cells were characterised by flow cytometry.
Human gut DC expressed AhR; expression was reduced in UC patients. Gut DC from UC patients exhibited an enhanced stimulatory capacity for T-cells that expressed higher levels of activation marker CD25 compared to T-cells stimulated by control DC. Gut DC in UC generated T-cells with enhanced expression of gut-homing markers β7 and CCR9, enhanced production of cytokines IL-10, IL-4 and IFN γ, but reduced production of TGF β. FICZ conditioning of gut DC reduced their stimulatory capacity for T-cells, and stimulated T-cells expressed lower levels of activation marker CD25, reduced expression of β7, reduced IL-10 production and T-bet expression, but increased production of TGF β, IL-17 and IL-22.
We demonstrate for the first time that human gut DC express AhR. The reduced AhR expression on gut DC in UC may partially account for enhanced DC-driven T-cell activation and enhanced T-cell production of UC-associated cytokines. AhR agonists may have therapeutic potential in UC by decreasing intestinal T-cell activation and migration to the gut, reducing production of UC-associated cytokines and increasing production of regulatory cytokines and cytokines generating intestinal epithelial barrier repair. Indeed, natural AhR agonists are a major component of cruciferous vegetables; epidemiological studies show high vegetable intake is associated with a decreased risk of IBD. The AhR provides a major link between the environment and UC pathogenesis, and natural AhR agonists provide a safe option for human intervention studies.