Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

The enzyme indoleamine 2,3‐dioxygenase 1 ( IDO 1) catalyses the initial, rate‐limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO 1's catalytic function has long been considered as the one mechanism responsible for IDO 1‐dependent immune suppression by dendritic cells ( DC s), which are master regulators of the balance between immunity and tolerance. However, IDO 1 also harbours immunoreceptor tyrosine‐based inhibitory motifs, ( ITIM 1 and ITIM 2), that, once phosphorylated, bind protein tyrosine phosphatases, ( SHP ‐1 and SHP ‐2), and thus trigger an immunoregulatory signalling in DC s. This mechanism leads to sustained IDO 1 expression, in a feedforward loop, which is particularly important in restraining autoimmunity and chronic inflammation. Yet, under specific conditions requiring that early and protective inflammation be unrelieved, tyrosine‐phosphorylated ITIM s will instead bind the suppressor of cytokine signalling 3 ( SOCS 3), which drives IDO 1 proteasomal degradation and shortens the enzyme half‐life. To dissect any differential roles of the two IDO 1's ITIM s, we generated protein mutants by replacing one or both ITIM ‐associated tyrosines with phospho‐mimicking glutamic acid residues. Although all mutants lost their enzymic activity, the ITIM 1 – but not ITIM 2 mutant – did bind SHP s and conferred immunosuppressive effects on DC s, making cells capable of restraining an antigen‐specific response in vivo . Conversely, the ITIM 2 mutant would preferentially bind SOCS 3, and IDO 1's degradation was accelerated. Thus, it is the selective phosphorylation of either ITIM that controls the duration of IDO 1 expression and function, in that it dictates whether enhanced tolerogenic signalling or shutdown of IDO 1‐dependent events will occur in a local microenvironment.