The SOCS3-Independent Expression of IDO2 Supports the Homeostatic Generation of T Regulatory Cells by Human Dendritic Cells

Abstract

Dendritic cells (DC) are professional antigen-presenting cells that have a role in the initiation of adaptive immune responses and tolerance. Among the tolerogenic mechanisms, the expression of the enzyme indoleamine 2,3-dioxygenase (IDO1) represents an effective tool to generate T regulatory cells (Treg). In humans, different DC subsets express IDO1, but less is known about the IDO1-related enzyme, IDO2. Here, we found a different pattern of expression and regulation between IDO1 and IDO2 in human circulating DC. At the protein level, IDO1 is expressed only in circulating myeloid DC (mDC) and is modulated by PGE2, whereas IDO2 is expressed in both mDC and plasmacytoid DC (pDC) and is not modulated by PGE2. In healthy subjects, IDO1 expression requires the presence of PGE2 and needs continuous transcription and translation, whereas IDO2 expression is constitutive, independent from SOCS3 activity. Conversely, in patients suffering from inflammatory arthritis, circulating DC express both IDO1 and IDO2. At the functional level, both mDC and pDC generate Treg through an IDO1/IDO2-dependent mechanism. We conclude that, in humans, while IDO1 provides an additional mechanism of tolerance induced by proinflammatory mediators, IDO2 is stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DC.

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…One notable feature of IDO2-deficient mice is a deficiency in their ability to support IDO1-induced T regulatory cells (Metz et al, 2014). Parallel evidence of a similar tolerizing function for IDO2 in human dendritic cells has been reported (Trabanelli et al , 2014). IDO1-deficient mice have also been found to be mosaic-deficient for IDO2 function, strengthening clues of IDO1–IDO2 interaction in immune control (Metz et al, 2014).…”

Role of indoleamine 2,3-dioxygenase in health and disease

“…These enzymes are capable of exhibiting similar [23,24,35], opposing [37,38] or co-operative [25] biological actions. Furthermore, although it is clear that targeting IDO1 activity with the D-or L-isomers of 1-MT underlies the ability of the drug to modulate numerous physiological and pathophysiological conditions in experimental animals, questions regarding the specificity of 1-MT (and other IDO1-targeted small-molecule inhibitors) for IDO1 compared with IDO2 both in vitro and in vivo remain to be clarified.…”

“…For example, in human DC subtypes [35], IDO2 is primarily found in the cerebral cortex, kidney, epididymis and testis, and in the liver of mice, and, in these tissues, IDO2 is often present in cells that are distinct from those expressing IDO1 [31,33,36]. These data suggest differential and non-redundant functions of IDO2 in vivo that are only now beginning to be revealed.…”

“…For instance, recent data support the suggestion that IDO2, but not IDO1, is linked to the pathogenesis of arthritis in mice by promoting the production of autoantibodies [37], whereas, unlike IDO1, IDO2 is not involved in the progression of inflammatory skin cancer in a mouse model [38]. Despite this discrepancy in the roles of IDO1 and IDO2, IDO2 can act similarly to IDO1 in promoting the generation of immunosuppressive Tregs (regulatory T-cells) and Ido1 and Ido2 gene-deficient mice both exhibit reduced skin-contact hypersensitivity responses [35,38]. In fact, a recent study found that IDO1-dependent generation of immunosuppressive Tregs is impaired in Ido2 gene-deficient mice [38], suggestive of a co-operative interaction of the two enzymes.…”

IDO2 Modulates T Cell–Dependent Autoimmune Responses through a B Cell–Intrinsic Mechanism

“…Mechanistically, IDO1 signals through the GCN2 and mTOR-mediated stress response pathways in response to Trp depletion (11–13). IDO2, a low-efficiency Trp-catabolizing enzyme, was only recently directly connected to immunomodulation (14–16) and less is known about the cellular and molecular mechanisms through which it influences immunity, though it is clear that IDO2 does not simply serve a redundant function to IDO1 (15). IDO2 expression is more restricted than IDO1, with high expression levels limited to liver, kidney, and cerebral cortex (17).…”