Summary: Interleukin (IL)-10 is a main player in peripheral immune tolerance, the physiological mechanism preventing immune reactions to self/harmless antigens. Here, we investigate IL-10-induced molecular mechanisms generating tolerogenic dendritic cells (tolDC) from monocytes. Using genomic studies, we show that IL-10 induces a pattern of accessible enhancers exploited by aryl hydrocarbon receptor (AHR) to promote expression of a set of core genes. We demonstrate that AHR activity occurs downstream of IL-10 signaling in myeloid cells and is required for the induction of tolerogenic activities in DC. Analyses of circulating DCs show that IL-10/AHR genomic signature is active in vivo in health. In multiple sclerosis patients, we instead observe significantly altered signature correlating with functional defects and reduced frequencies of IL-10-induced-tolDC in vitro and in vivo. Our studies identify molecular mechanisms controlling tolerogenic activities in human myeloid cells and may help in designing therapies to re-establish immune tolerance.
