Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses

Abstract

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function. Indeed, IDO2, like IDO1, is necessary for the differentiation of regulatory T cells in vitro . However, compared to IDO1, in vivo studies demonstrated a contrasting role for IDO2, with experiments in preclinical models of autoimmune arthritis establishing a proinflammatory role for IDO2 in mediating B and T cell activation driving autoimmune disease. Given their potentially opposing roles in inflammatory responses, interpretation of results obtained using IDO1 or IDO2 single knockout mice could be complicated by the expression of the other enzyme. Here we use IDO1 and IDO2 single and double knockout (dko) mice to define the differential roles of IDO1 and IDO2 in B cell-mediated immune responses. Autoreactive T and B cell responses and severity of joint inflammation were decreased in IDO2 ko, but not IDO1 ko arthritic mice. Dko mice had a reduction in the number of autoantibody secreting cells and severity of arthritis: however, percentages of differentiated T cells and their associated cytokines were not reduced compared to IDO1 ko or wild-type mice. These data suggest that autoreactive B cell responses are mediated by IDO2, while autoreactive T cell responses are indirectly affected by IDO1 expression in the IDO2 ko mice. IDO2 also influenced antibody responses in models of influenza infection and immunization with T cell-independent type II antigens. Taken together, these studies provide evidence for the contrasting roles IDO1 and IDO2 play in immune responses, with IDO1 mediating T cell suppressive effects and IDO2 working directly in B cells as a proinflammatory mediator of B cell responses.

An Insight into the Roles of Dietary Tryptophan and Its Metabolites in Intestinal Inflammation and Inflammatory Bowel Disease

“…[ 52 ] IDO is an enzymatic system that includes two related but distinct enzymes, namely IDO1 and IDO2. [ 53 ] In the liver, the ingested Trp is mainly utilized under the catalysis of TDO enzyme, while in extrahepatic tissues, it is mainly metabolized by the catalytic action of the IDO enzyme. [ 53 ] During the catalysis of IDO and TDO enzymes, the ingested Trp is first degraded into N‐formylkynurenine by oxidizing the indole ring of Trp, which is subsequently hydrolyzed to KYN by formamidase.…”

“…[ 53 ] In the liver, the ingested Trp is mainly utilized under the catalysis of TDO enzyme, while in extrahepatic tissues, it is mainly metabolized by the catalytic action of the IDO enzyme. [ 53 ] During the catalysis of IDO and TDO enzymes, the ingested Trp is first degraded into N‐formylkynurenine by oxidizing the indole ring of Trp, which is subsequently hydrolyzed to KYN by formamidase. [ 54 ] Finally, KYN produced several biologically active molecules, such as kynurenic acid (Kna), 3‐HAA, and nicotinamide adenine dinucleotide (NAD + ) by the action of cascade of enzymes.…”

“…[64] Activation of the GCN2 signaling pathway with Trp depletion and KYN production has been implicated in the immune response by affecting the functions of immune cells. [53,65] For example, GCN2 deficiency significantly decreases T-cell activation and cytokine production, whereas GCN2 activation can promote cell autophagy and antigen cross-presentation, thereby enhancing virus-specific CD8 + T cell response. [66][67][68] Additionally, IDO1-mediated Trp depletion activates GCN2 signaling system that in turn triggers differentiation and recruitment of T-regs.…”

The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins

“…A closely related isoform (43% similar), referred as IDO2 [ 26 ], likely resulted from gene duplication, but is expressed in a very limited number of tissues, mainly liver, kidney and antigen-presenting cells in small amounts, and is also enzymatically much less active on Trp (~340-fold higher Km). It appears to have an accessory role in IDO1-mediated immune regulation and in inflammation [ 27 , 28 ]. In most literature, and in this review, the term IDO is to be considered synonymous to IDO1.…”

Investigating the effects of IDO1, PTGS2, and TGF-β1 overexpression on immunomodulatory properties of hTERT-MSCs and their extracellular vesicles

“…Although IDO1 and its homolog IDO2 are encoded by linked genes, their immunoregulatory features seem to be completely different. Whereas IDO1 mediates T-cell responses in the benefit of anti-inflammation, IDO2 mediates B-cell responses towards a pro-inflammatory phenotype 107 .…”