Schematic representation of ITIM-mediated signaling function of IDO. Tyrosine-phosphorylated IDO ITIMs (P) act as docking sites for tyrosine phosphatases (SHPs) and SOCS3. Association of IL-6-induced SOCS3 promotes IDO proteasomal degradation. TGF-β, by inducing SHPs and activating the tyrosine kinase Fyn that phosphorylates IDO ITIM domains, promotes the association of IDO with SHPs. IDO/SHPs complexes, via inhibition of IRAK1, activate the noncanonical NF-κB pathway (p52/RelB), which in turn induces the production of type I IFNs (IFNα/β) and TGF-β, which synergize with noncanonical NF-κB in upregulating Ido1 expression.