A novel kynurenine-dependent circuit in DC1 promote IDO1 expression in DC2 leading to experimental autoimmune encephalomyelitis suppression

Abstract

Abstract Classical dendritic cells (cDCs) are professional antigen-presenting cells that play a key role in shaping appropriate immune responses. DCs are a potent T cell activators but they are also involved in maintaining immune homeostasis and self-tolerance. DCs can be classified into three major types: pDC, DC1 and DC2. One mechanism by which DCs regulate tolerance involves indoleamine 2,3-dioxygenase 1 (IDO1) a tryptophan (Trp) metabolizing enzyme. In this study, we analyzed the ability of L-Kyn to induce tolerogenic IDO1 pathway in different DCs subsets in vitro and in vivo model of experimental autoimmune encephalomyelitis (EAE). We show that inflammatory stimuli, like LPS, was able to induce IDO1 only in DC1, but not in DC2 or pDC, when DCs were treated as isolated cultures. In contrast, when LPS was added to cultures containing all three DC subsets, LPS could also induce IDO1 expression in DC2, which acquired tolerogenic function. Induction of IDO1 in DC2 involved a novel DC1-DC2 communication pathway mediated by a Kyn-AhR-RelB axis. Kynurenine produced by DC1 activates AhR in DC2 inducing IDO1 in a RelB-dependent manner. In vitro L-Kyn treatment impaired DC2 T cells priming ability causing suppression of MOG-specific reactivity with an increment of Foxp3+ CD4+ T cells. In vivo, oral administration of L-Kyn induces functional Treg cells that suppress EAE and this effect is completely abrogated in Ahrflox/floxCD11C Cre+ mice. These data suggest that in specific microenvironments, small numbers of IDO1-expressing DC1 may spread tolerogenic activity to DC2 cells through a kynurenine-AhR axis and L-Kyn could constituting a unique endogenous molecule for therapeutic immunomodulation of inflammatory and autoimmune diseases.