Functional plasticity in DCs allows these cells to present antigen in an immunogenic or tolerogenic fashion, largely contingent on environmental factors [[39]]. Among those, costimulatory and coinhibitory interactions between DCs and T cells are pivotal in tipping the balance between immunity and tolerance in favor of either outcome. Originally thought selleckchem to selectively deliver inhibitory signals to T cells when engaged by CD80/CD86 molecules

on DCs, the surface T-cell receptor CTLA-4 (widely expressed by Treg cells) was later shown to behave as an activating ligand itself for CD80/CD86 “receptors” capable of transduction, resulting in intracellular signaling events. Through an as-yet-unidentified signaling cascade, DCs release type I and type II IFNs (depending on DC subsets) that act in an autocrine and paracrine fashion to induce strong IDO expression and function [[31]]. This might exemplify a mechanism whereby natural or induced Treg cells became engaged in controlling acute hyperinflammatory or allergic reactions in local tissue microenvironments [[40]]. Kynurenine-dependent, AhR-driven T-cell differentiation would then contribute to expand the pool of Treg cells [[6]]. However,

it became soon apparent that, in the long-term control of immune homeostasis and tolerance to self, IDO relies on different regulatory stimuli and cytokines, providing a basal function amenable to regulation by abrupt environmental changes [[41]]. The immunoreceptor tyrosine-based

inhibitory motifs (ITIMs) are known to signal via recruitment and activation of Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1), SHP-2, Inhibitor Library molecular weight and inositol polyphosphate-5-phosphatase D (SHIP), as shown in Fig. 1. A prototypic ITIM has the I/V/L/SxYxxL/V/F Alanine-glyoxylate transaminase sequence, where x denotes any amino acid and Y the phosphorylable tyrosine [[42, 43]]. In inflammation, phosphorylated ITIMs in IDO interact with suppressor of cytokine signaling 3 (SOCS3), resulting in proteasomal degradation of the enzyme [[30, 44]]. Two ITIMs are present in mouse and human IDOs, which, in the presence of proinflammatory IL-6, lead to SOCS3-dependent proteasomal degradation of the enzyme. This has been considered to be an important mechanism whereby the proinflammatory cytokine IL-6 interrupts tolerance in several acute responses to danger signals [[45]]. In contrast, in a TGF-β–dominated environment and in the absence of IL-6, Fyn-mediated phosphorylation of IDO activates a variety of downstream signaling effectors — including SHPs and noncanonical NF-κB — that further sustain TGF-β production, production of type I IFNs, and favor a bias of the pDCs toward a regulatory phenotype [[46-48]]. By means of this mechanism [[15, 49]], IDO enhances its own expression and stably tips the balance between canonical (i.e. proinflammatory) and noncanonical (antiinflammatory) NF-κB activation in favor of the latter [[50]].