The human IDO1 gene is encoded on 10 exons which span 14,163 bps at chromosome 8p12-p11 (nucleotides 39,890,485-39,905,107). The murine IDO1 gene is similarly sized and localized to a syntenic locus on mouse chromosome 8A2.

Transcription of the human IDO1 gene produces a full-length mRNA transcript of 1,572 nt. The promoter includes transcription factor sites that confer responsiveness to type I and type II interferons (IFN-alpha / IFN-beta and IFN-gamma respectively), most potently to IFN-gamma. Many cell types strongly increase IDO transcription after exposure to IFN-gamma, including myeloid cells (monocyte/macrophages and dentritic cells), fibroblasts, endothelial cells, epithelial cells and many tumor cell lines. STAT and IRF transcription factors function cooperatively to mediate induction of IDO1 expression by IFN-gamma, and mice lacking either IFN-gamma or IRF1 function are deficient in IDO1 expression during infections.

None known.

The IDO1 gene encodes a full-length protein of 403 amino acids with a predicted molecular weight of 45,332 Daltons. The open reading frame is preceded by a long, untranslated sequence. There is no Kozak consensus sequence present at the ATG start site in the open reading frame.

IDO1 is widely expressed in the body. High expression is seen in placental trophoblast giant cells of fetal origin, epididymis, gut (distal ileum and colon), lymph nodes, spleen, thymus and lung. IDO activity in many of these locations is markedly increased in vivo by LPS treatment. With the exception of epididymis, a common feature of sites of expression are extensive mucosal surfaces and/or large lymphoid compartments with immunoregulatory roles. IDO1 is overexpressed in many human diseases including cancer, chronic infectious disease, allergy, autoimmune disease and other disorders characterized by local immune suppression.

IDO1 is a cytosolic enzyme with no known secreted or extracellular form.

IDO1 is a single-chain oxidoreductase catalyzing the first, rate-limiting step of tryptophan degradation in biosynthesis of the central metabolic regulator nicotinamide adenine dinucleotide (NAD) along the kynurenine pathway. In mammals, IDO1 does not catabolyze excess dietary tryptophan, which is carried out by the liver enzyme TDO2, and NAD levels are not maintained by synthesis but by salvage from the diet. Thus, the role of IDO1 in mammals was obscure until it was discovered to be strongly induced by IFN-gamma and linked to immune control. The function of IDO1 in immune control is based on broad evidence that tryptophan depletion and/or kynurenine production suppresses T cell-mediated immunity. In particular, IDO1-mediated tryptophan catabolism in antigen-presenting dendritic cells appears to be an important mechanism to generate immune tolerance to cross-presented neoantigens, such as those that arise during allogeneic pregnancy or cancer.
Antiproliferation : Tryptophan catabolism by IDO1 has been suggested to mediate antiproliferative effects during infection, including directly on infectious microorganisms that may rely on tryptophan for growth. With regard to the function of IDO1 in immune regulation, tryptophan depletion in the vicinity of an antigen presentation event has been suggested to limit T cell activation by preventing the cell division required by T cells to become activated upon appropriate presentation of antigen. Dendritic cells arising from monocytes acquire the ability to act as regulatory cells that suppress T cell proliferation through tryptophan catabolism by IDO1. The 1-methyl analogue of tryptophan (1MT) has been used widely to block IDO activity. When T cells are deprived of tryptophan, they arrest at a mid-G1 phase of the cell cycle. Restoring tryptophan does not restore the activation process, which requires a second round of T cell receptor signaling along with tryptophan. Together this information has suggested that antigen-presenting cells can employ IDO1 to restrict T cell activation by blocking T cell proliferation, due to tryptophan catabolism.
Apoptosis : The products of tryptophan catabolism by IDO1 include kynurenine and downstream products of the so-called kynurenine pathway that can induce apoptosis of thymocytes and Th1 but not Th2 helper T cells. Apoptosis induced by these products does not require Fas/Fas ligand interactions but are associated with activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, some kynurenines can deplete specific thymocyte subsets like dexamethasone. Thus, the selective deletion of T lymphocytes by kynurenine production has been suggested as one mechanism through which tryptophan catabolism could blunt immunity under pathologic conditions.
Immune tolerance : Many studies illustrate how IDO1 overexpression can blunt immune responses to neoantigens. Cell lines overexpressing IDO1 limit antigen-specific T cell responses in vitro. In murine tumor cell lines, IDO1 overexpression renders tumor allografts resistant to immune rejection in vivo. Adenoviral-mediated IDO1 gene transfer into pancreatic islet cells is reported to prolong survival in allogeneic hosts. Similarly, ectopic expression of IDO1 is found to protect allogeneic lung transplants from rejection. CTLA-4 signaling induces IDO and pre-treatment of mice with CTLA-4-Ig to induce IDO expression suppresses rejection of pancreatic islet allografts. In a model of graft-versus-host disease, IDO1 overexpression completely blocks clonal expansion of alloreactive T-cell receptor (TCR)-transgenic T cells. Studies in other tissue allograft models confirm that IDO is a potent regulator of adaptive immune response. A consistent picture is provided by studies employing the pharmacological agent 1MT as an IDO inhibitor. 1MT exacerbates symptoms of experimental autoimmune encephalomyelitis and abrogates the tolerogenic effects of CTLA4-Ig treatment in an islet-cell transplant model. Similarly, 1MT increases disease severity and mortality in a T cell-dependent colitis model, suggesting the role of IDO in the downregulation of Th1 responses within the gastrointestinal tract. Lastly, as discussed in more detail below, 1MT corrects immune escape mediated by IDO in a variety of allograft and transgenic (autochthonous) mouse models of cancer.
Maintenance of Pregnancy : IDO1 has been suggested to mediate immune tolerance during pregnancy on the basis of the ability of IDO inhibitor 1MT to act as an abortifacient in allogeneic but not syngeneic mice. IDO1 gene knockout studies do not replicate this effect suggesting a compensatory genetic effect or an IDO1-dependent effect of 1MT. Indeed, 1MT is no longer active in IDO1 knockout mice, demonstrating that 1MT must target IDO1 mediate its effects.
Null phenotype in mouse : IDO1-deficient mice are viable and fertile. in vitro generation of antigen-presenting dendritic cells (DCs) from IDO1-deficient bone marrow precursors appeared to be affected in the presence of GM-CSF, however, changing growth factor and adherence conditions abolished the observed differences (Flt3L and low-adherence dishes). Moreover, IDO1-deficient mice display a normal DC compartment in vivo and do not develop lethal autoimmune or lymphoproliferative disorders. Consistent with this observation, mice treated systemically for up to 28 days with 1MT or other IDO inhibitors do not appear to develop spontaneous autoimmunity. Together these observations imply that IDO1 is non-essential for self tolerance. In contrast, skin carcinogenesis studies reveal that IDO1-deficient mice are resistant to cancer initiation and carcinoma progression, due to an apparent inability to develop tumor tolerance.

Human IDO1 has 62% identity (77% similarity) with mouse IDO1 and 44% identity (64% similarity) with mouse IDO2. Human IDO1 has 44% identity (63% similarity) with human IDO2 and mouse IDO1 has 44% identity (64% similarity) with mouse IDO2.