PGE₂-Independent Expression of Indoleamine 2,3-Dioxygenase-2 (IDO2) Supports the Tolerogenic Function of Monocyte-Derived Dendritic Cells,

Abstract 3231

The indoleamine 2,3-dioxygenases IDO1 and IDO2 participate in tryptophan catabolism along the kynurenine pathway and are specifically inhibited by 1-methyltryptophan (1-MT). IDO1 expression in dendritic cells (DCs) is upregulated by various maturation stimuli. In particular, PGE₂ plays a crucial role in inducing IDO1-expressing DCs. While it is well established that IDO1-expressing DCs contribute to immunological tolerance by a number of mechanisms, little is known about the expression, function and regulation of IDO2 in DCs.

Here we show that immature monocyte-derived DCs (Mo-DCs) express IDO2 which, like IDO1, is also upregulated upon maturation with a prostaglandin-E2 (PGE₂)-containing cytokine cocktail. However, while IDO1 upregulation is strictly dependent on PGE₂ during maturation, IDO2 expression level is not affected by PGE₂. We show that IDO2 expressed by Mo-DCs is enzymatically active, producing L-kynurenine, and that this activity affects T-cell functions by inhibiting allogeneic and autologous T-cell proliferation and by inducing formation of a population of T regulatory cells (T_regs). Taken together, our findings establish different regulatory pathways for IDO2 and IDO1 in Mo-DCs, where IDO2 is functionally active, and they demonstrate that the tolerogenic function of Mo-DCs relies in part on PGE₂-independent expression of IDO2.