W1 - Aryl Hydrocarbon Receptor Activity is Required Downstream IL-10 Signaling to Promote Regulatory Functions in Human Dendritic Cells

Abstract Text: Peripheral immune tolerance is a key physiological mechanism preventing immune reactions to self and harmless antigens. Interleukin (IL)-10 plays key roles in this system by inhibiting effector cells and instructing regulatory cells. Here, we investigated the mechanisms underlying IL-10-mediated induction of regulatory activity in human dendritic cells (DC). Using chromatin and transcriptomic studies in tolerogenic IL-10-induced monocyte-derived DC, we show that IL-10 induces a pattern of accessible enhancers that are exploited by Aryl Hydrocarbon Receptor (AHR) to promote the expression of a set of core genes. For the first time, we demonstrate that AHR acts downstream of IL-10 signaling in myeloid cells and that its activity is required for the establishment of IL-10-induced core genes and induction of tolerogenic activities in DC. Analyses of tolerogenic DC in peripheral blood show that the IL-10/AHR genomic signature is active in vivo in healthy conditions. In multiple sclerosis patients we instead observe significant alterations in this signature that correlated with functional defects and reduced frequencies of IL-10-induced tolerogenic DC in vitro and in vivo. Our studies reveal previously undescribed IL-10-induced molecular mechanisms required for establishing tolerogenic activities in human myeloid cells and may help in designing new therapies to re-establish immune tolerance.