Figure 2: T-cell immune regulation by IDO1. (a) IDO1 is induced by IFN-γ-dependent and/or -independent signal pathways, depending on the variety of immune stimuli by macrophages and dendritic cells (DCs) [28, 83]. IDO1 activity is suppressed by the formation of NO or the competitive enzyme inhibitor, 1MT. Marked increases in IDO1 suppress immune responses by locally depleting L-TRP and preventing T-cell proliferation [44]. Expression of IDO1 has been observed in certain types of activated macrophages and DCs. IDO1-expressing cells deplete TRP from the extracellular milieu and secrete TRP metabolites, including KYN, 3-HK, 3-HAA, and QUIN, which induce T-cell apoptosis and suppress immune responses in vitro. (b) CD19+ plasmacytoid DCs (pDCs) express high levels of IDO1, which can activate mature regulatory T (Treg) cells via activation of the protein kinase general control nonderepressing-2 (GCN2) pathway of protein synthesis inhibition [84]. pDC-produced IDO1 and activated Treg can convert naïve T cells into new Treg. IDO1 acts in an autocrine manner to suppress pDC production of IL-6, which prevents the conversion of Treg into IL-17-producing Th17 proinflammatory cells [79]. IDO1 also downregulates type I IFN (IFN-α) production by pDC [80].