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The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity
Open accessAbstract
Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called “kynurenines” that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity and the rejection of transplanted tissues. Finally, we examine how vaccines may enhance immune suppression of autoimmunity through the upregulation of IDO biosynthesis in human dendritic cells.
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![Figure 2 Mechanism of IDO1 induction in dendritic cells: transcription and translation. Several molecular stimuli and signaling pathways were shown to induce the transcription and translation of metabolically-active IDO1 enzyme [35,40,50]. The IDO1 promoter contains nucleotide sequences that allow regulation of transcription through interferon sequence response-like element (ISRE) upstream consensus sequences, GAS (palindromic gamma-activated sequences) and non-canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) [42,50]. In addition, the IDO1 promoter region contains three partial non-canonical RelB/p52 binding sites: AGGAGACACA, GGGAGACAGA and AGGAGAAAGA located near position −2000, which is located downstream of NF-κB-driven IDO upregulation following stimulation of the TLR4, INFGR, IFNAR, TNFR and CD40R signaling pathways [43].](/paper-figures/c748b5e2d686409aba397c4eb47122fd/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-2.jpg)
![Figure 3 The TGF-β-IDO-SHP axis. The TGF-β-IDO-SHP axis activates the non-canonical NF-κB pathway [49]. In splenocytes, SHP-1 inhibits the protein kinase IRAK1 and tips the balance of activation of the canonical versus non-canonical NF-κB signaling pathway in favor of the latter, resulting in upregulated production of type I interferon [49]. In addition to TGF-β, the aryl hydrocarbon receptor (AhR) has also been shown to play a role in IDO production [51,53]. Interestingly, kynurenines produced from IDO’s enzymatic activity can also bind and activate as an endogenous ligand, AhR [53,54]. Abbreviations: IFN (α β, γ,): interferon alpha, beta, gamma; TGF-β: transforming growth factor-beta; TNF: tumor necrosis factor; TLR4: toll-like receptor 4; TRAF: TNF-receptor associated factors; TRIF: TIR-domain-containing adapter-inducing interferon-β; SHP: orphan nuclear receptor small heterodimer partner; SMAD: extracellular signal transducers from TGF-β ligands to the nucleus; IRF (1, 3): and interferon regulatory factor 1,3.](/paper-figures/ded76164a88e4dc388ba105d8aa15574/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-3.jpg)
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“Increased IDO expression is responsible for the catabolism of TRP in the KYN degradation pathway [36] and is canonically upregulated by inflammatory mechanisms [37,38].”
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MiR-669b-3p regulates CD4+ T cell function by down-regulating indoleamine-2, 3-dioxygenase
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“In HIV/TB co-infection, elevated kynure-nine pathway activity could compromise immune response effectiveness (Mbongue et al., 2015).”
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“identified indoleamine 2,3dioxygenase that was highly induced in poly(I:C)-treated astrocytes, an enzyme with many biological functions, especially immunosuppression (192) through the synthesis of tryptophan metabolites that are cytotoxic to certain immune cells (193).”
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“, via the induction of type I interferons, which, in turn, induce TGFb and IDO expression (60).”
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“IDO as well as PD-L1 also inhibit T-cell activation [22, 26, 27] PD-L1 expression in Mreg IFNγ0 , the same percentage of Mreg and Mreg IFNγ0 are positive for PD-L1 on protein level.”
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“Downregulate kynurenic acid metabolism through Treg-mediated Foxp3 apoptosis of CD4+T cells Reduce L-arginine concentration essential for normal T-cell functions via the production of nitric oxide (NO) using nitric oxide synthase (NOS) Induce expression of cytotoxic CD8-T lymphocytes and release anti-apoptotic signals…”
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“As such, it regulates the overall rate at which downstream Kyn metabolites are produced, thereby justifying their designation as the rate-limiting enzymes of the Trp–Kyn pathway [25].”
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“The role of IDO has been extensively investigated in various diseases, including cancer [3,6–15], autoimmune disorders [16,17], and neurodegenerative conditions [18,19].”
BackgroundDelivery of Immobilized IFN-γ With PCN-333 and Its Effect on Human Mesenchymal Stem Cells.
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“Normally, IDO is expressed during immunosuppressive processes via inhibition of pro-inflammatory T-cells as well as induction of the regulatory T-cell population [43].”
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“For example, TGF-β can suppress the cytotoxic activity of γδ T cells, while Indoleamine 2,3-Dioxygenase 1 (IDO)- mediated tryptophan depletion can impair MAIT cell function [88,89].”
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“Specifically, IKK α induces the non-canonical NF-κ B pathway by promoting the processing of p100 into p52, leading to the formation of the p52/RelB transcriptional complex, which governs immune and inflammatory responses (Mbongue et al., 2015; Pallotta et al., 2011).”
Identification of crucial inflammaging related risk factors in multiple sclerosis
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“The roles of the kynurenine pathway included endogenous regulation of neuronal excitability, initiation of immune tolerance and synthesis of nicotinamide adenine dinucleotide (NAD), where NAD + being a key molecule in a variety of biochemical processes (Mbongue et al., 2015; Zhong et al., 2023).”
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“T cells, NK cells, and macrophages, activates regulatory T cells, and has positive effects on tumor progression (Mbongue et al., 2015; Zhai et al., 2020).”
BackgroundIndolamine 2,3-dioxygenase (IDO) inhibitors as a potential treatment for somatic symptoms
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Activation of GSK3 Prevents Termination of TNF-Induced Signaling
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Amino Acids | Aromatic Amino Acid Metabolism Across Species
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“Further analysis identified correlations in the CNS between the expression of IDO mRNA and inflammatory cytokine gene expression following VEEV TC-83 inoculation in WT and Tg2576 mice.”
BackgroundHarnessing IDO inhibitors to optimize cancer immunotherapy
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“The primary role of IDO in the TME is to break down the necessary amino acid tryptophan into kynurenine, which significantly affects immune modulation (Mbongue et al. 2015) (Fig.”
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“Conversely, green tea extracts have been shown to enhance the release of indoleamine-2,3-dioxygenase, which plays a critical role in suppressing immune responses to bacteria [33, 34].”
Indoleamine 2,3-Dioxygenase 1 (IDO1) in Kidney Transplantation: A Guardian against Rejection
Wiśnicki, K., Donizy, P., Hałoń, A., Wawrzonkowski, P., Janczak, D., Krajewska, M., & Banasik, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12247531 · Cited by 3
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“, the catabolism of the essential amino acid tryptophan (Trp) along the kynurenine pathway (KP) has been reported to play a crucial role in regulation of the immune response [13,14].”
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“…acid tryptophan into anthranilic acid and kynurenine (Sugimoto et al., 2006), has been mainly studied in pregnancy, organ transplantation, autoimmune diseases, tissue inflammation and tumors (Curti et al., 2009; Liu et al., 2014; Mbongue et al., 2015; Mellor et al., 2002; Thaker et al., 2013).”
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Kynurenine pathway impact on immune evasion and inflammation in acute myeloid leukemia
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Molecular Markers Distinguishing Early‐Stage Mycosis Fungoides From Atopic Dermatitis Skin Lesions
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“IDO has immunosuppressive roles not only in the context of cancer but also in organ transplantation and protection of the placenta during pregnancy [66–68].”
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“Functioning as a metabolic checkpoint inhibitor, IDO1 blockade is increasingly being evaluated in combination with conventional cytotoxic treatments to improve clinical efficacy [ 11, 12].”
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“Indoleamine 2, 3-dioxygenase (IDO) expression, an effector of immune suppression and autoimmunity [257], was found enriched in stromal and endothelial cells and positively correlated with higher immune cell density in both primary tumors and their metastases, independently of NE patterns [256].”
Capatina, A. L., Czechowski, T., Plunkett-Jones, C., Tonon, T., Kourtzelis, I., Lichman, B. R., Brackenbury, W. J., Graham, I. A., & Lagos, D. (2026) · Biochemical Journal · doi:10.1042/bcj20253246 · Cited by 1
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“The synthesis of kynurenine through the actions of the immunosuppressive enzymes IDO and TDO constitutes a primary physiological mechanism for the degradation of tryptophan (Trp) (Ebokaiwe et al., 2022; Mbongue et al., 2015).”
Peixoto, D., Carvalho, I., Robledo, D., Machado, M., Pereiro, P., Figueras, A. J., Azeredo, R., & Costas, B. (2025) · Scientific Reports · doi:10.1038/s41598-025-01079-y · Cited by 1
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“IDO is the rate-limiting enzyme in the tryptophan catabolic pathway and is regarded as one of the key modulators of acquired immune tolerance [55].”
BackgroundExploring the Potential of Plant-Based CTB-INS Oral Vaccines in Treating Type 1 Diabetes
Mbongue, J. C., Vanterpool, E., & Langridge, W. (2023) · Immuno · doi:10.3390/immuno3020014 · Cited by 2
“Since tryptophan must be received through diet, managing how it is metabolized can significantly affect how the body uses energy and how the immune system responds [58].”
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“Intracellular Ido Assay Indoleamine 2,3-dioxygenase (IDO) is a cytosolic heme protein that is important for immuno-regulatory functions [Takikawa et al., 1988; Mbongue et al., 2015].”
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“Но в то же время, продвинутые метаболиты катаболизма триптофана такие как QUIN (quinolinic acid) и 3-HAA (3-hydroxyanthranilic acid) обладают выраженным нейротоксическим эффектом, который лежит в основе развития таких заболеваний, как болезни Альцгеймера, Хантингтона, развития депрессивных состояний при различных восп…”
InfluentialGong, Y., Zeng, W., Liao, Y., Xie, X., Qin, Z., Li, C., & Zhang, X. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1926935 · Cited by 1
“…, which inhibit the production of RANKL and TNF-a by pro-in fl ammatory cells; more importantly, Tregs express CTLA-4, which can bind to CD80/CD86 on the surface of osteoclast precursors or antigen-presenting cells, thereby directly inhibiting osteoclastogenesis or inducing the IDO pathway (61, 62).”
Lénárt, I., Horváth, O., Molnár, K., Bereczki, C., Monostori, P., Klivényi, P., & Galla, Z. (2026) · Scientific Reports · doi:10.1038/s41598-026-55891-1 · Cited by 1
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Indoleamine 2,3-Dioxygenase: A Potential Biomarker for Neural Damage Severity of Leprosy Neuropathy
Rahman, A. U., Santana, R. C., Pereira, M. M. D. P., Moura, C., de Oliveira, J. D., Sarno, E., da Silva, G. M. S., Jardim, M., & Pinheiro, R. O. (2026) · Cellular and molecular neurobiology · doi:10.1007/s10571-025-01657-8 · Cited by 1
“It catalyzes the conversion of tryptophan into kynurenine, thereby regulating tryptophan availability for various cellular and biological processes (Merlo et al. 2022 ; Mbongue et al. 2015).”
Paulino, P. J. I. V., & Omar, M. T. C. (2025) · Journal of Genetic Engineering and Biotechnology · doi:10.1016/j.jgeb.2025.100574 · Cited by 1
“52 Meanwhile, GZMB genes is associated with munity in cancer, 53 suggesting its role in the tumor microenvironment.”
Nguyen, T. S., Nguyen, T. T. N., Nguyen, T., Ha, T. B. C., Nguyen, M. C., Raza, S. S., Do, V. T., & Chu, H. H. (2025) · Stem Cells International · doi:10.1155/sci/6612312 · Cited by 1
“These cytokine-rich conditions diminish key immunomodulatory mechanisms, such as indolea-mine-2,3-dioxygenase, prostaglandin E 2 , and TGF-β , down-regulates migratory CXCR4/SDF-1 signaling and diminish MSC survival in vivo, collectively eroding their immunomodulatory ef fi cacy [84 – 87].”
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“Members of the tumour necrosis factor superfamily possess the capability to initiate signalling processes that can either promote or sustain the expression of indoleamine 2,3-dioxygenase 1 (IDO1) [13].”
Effects of rubiadin-3-methyl ether on the immune properties of hUC-MSCs
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Will Mesenchymal Stem Cell Therapy Be Effective In COVID-19?
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“, 2005) and has been shown to activate indoleamine 2,3-dioxygenase 1 (IDO1) biosynthesis (Mbongue et al., 2015; Y. Shi & Massague, 2003).”
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“IDO is a potent immunosuppressive enzyme which induces catabolism of tryptophan in to pro-apoptotic metabolites, resulting in the suppression of effector cells [158].”
BackgroundImmunoparasitology: A Unique Interplay Between Host and Pathogen
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“For example, Rzepecka et al. reported that a synthetic analog of ES-62 known as SMA12b is able to suppress arthritis in mice by prevention of inflammasome activation (132).”
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Shotgun proteomic analysis of quail liver under feed deprivation and low-energy diet conditions
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“…with amino acid and lipid metabolism, indicating that the liver actively processes diverse substrates, including amino acids and organic acids, under normal conditions (Cogburn et al., 2020; Fujikawa et al., 2024; Li et al., 2024; Mbongue et al., 2015; Rengaraj et al., 2013; Xu et al., 2008).”
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“38 Albumin also exerts antioxidant effects via its cysteine-34 residue.”
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“This TGF-b /IDO/SHP signalling axis drives non-canonical nuclear factor-k B (NF-k B) activation through p52/ReIB pathway, in part by suppressing interleukin-1 receptor-associated kinase 1 (IRAK1), thereby preventing transcriptional induction of IL-6 (82).”
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Immune tolerance: Parallels between pregnancy and kidney transplantation.
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The interplay between microbiota and the gut-brain axis in treatment-resistant depression
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The evolving landscape of immunotherapy in lung cancer: From mechanism to clinical translation
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Metadata
- Authors
- Mbongue, J., Nicholas, D., Torrez, T., Kim, N.-S., Firek, A., & Langridge, W.
- Affiliations
- Loma Linda University (US)
- California Baptist University (US)
- Jerry L. Pettis Memorial VA Medical Center (US)
- Corresponding author
- Langridge, William
- Venue
- Vaccines
- Publisher
- MDPI AG
- Published
- 2015-09-10
- Volume
- 3
- Issue
- 3
- Pages
- 703-729
- ISSN
- 2076-393X (ISSN-L)
- PMC
- PMC4586474
- OpenAlex
- W2101376945
- Cited by
- 351
- References
- 165
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 32 · 2023: 39 · 2022: 43 · 2021: 39 · 2020: 47 · 2019: 34 · 2018: 39 · 2017: 16 · 2016: 11 · 2015: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Vaccines (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Loma Linda University
- National Institutes of Health (DK-99-013)
- National Institute of General Medical Sciences (R25GM060507)
- National Institute on Minority Health and Health Disparities (P20MD006988)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- indoleamine 2,3-dioxygenase, tryptophan catabolism, kynurenine, immunosuppression, autoimmunity, dendritic cells, tumor immunosuppression, allergy, graft rejection, inflammation, vaccine adjuvants, tryptophan metabolism
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