Indoleamine 2,3-dioxygenase 1 (IDO1): relationship between functions and intracellular localization

Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytoplasmic, tryptophan catabolizing enzyme that promotes fetomaternal tolerance in mammalian pregnancy, and it exerts regulatory functions in autoimmune and inflammatory settings [1]. Its regulation, as well as its mechanisms of action as an immune regulator, is composite [2] and involves tryptophan deprivation, production of immunosuppressive metabolites (kynurenines) and activation of signaling events. In particular, we previously found that, in a microenvironment dominated by the cytokine TGF-?, IDO1 is involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in plasmacytoid dendritic cells (pDCs), a rare yet highly important DC subset. In contrary, the IDO1-mediated immunosuppressive function in pDCs induced by the cytokine IFN-?, i.e., the standard IDO1 inducer, depends on its catalytic function [3]. We here investigated whether the distinct IDO1 mechanisms may correlate with a differential cellular localization of the enzyme. In accordance with literature data, we confirmed that, in pDCs, the IDO1 protein has a main cytoplasmic localization, although we also detected the presence of a significant amount of IDO1 in subcellular structures (endosomes) other than cytoplasm, particularly in cells treated with TGF-?. Intriguingly, in pDCs treated with TGF-?, we also found IDO1 being released in the extracellular milieu. similarly to what observed in stem cells from human amniotic fluids [4]. Therefore, our data further underlined the biologic complexity of a powerful immune regulator such as iDO1.