Tryptophan, IDO and Your T Cells

Tryptophan is an essential amino acid: your body cannot make it, so all of it comes from protein in your diet¹. Most people know it as the raw material for serotonin, but that is a minor route. About 95% of the tryptophan your body breaks down goes through a different chain of reactions, the kynurenine pathway².

Outside the liver, the first step of that pathway is run by an enzyme called indoleamine 2,3-dioxygenase, or IDO, and the immune system controls it². When IDO is switched on, it drains tryptophan from its surroundings and releases breakdown products called kynurenines. Together these act as a brake on T cells, the white blood cells that recognise specific threats and either attack them or direct the rest of the immune response. That brake helps protect a pregnancy and keep immune responses in proportion, but tumours and chronic infections can exploit it³.

This guide walks through the research, from the 1998 mouse study that put IDO on the map to a large cancer trial that failed in 2019, and explains what it does and does not mean for L-tryptophan and other supplements.

Once absorbed, tryptophan has several jobs:

• Building proteins. Like every amino acid, it is built into the body's proteins¹.
• Serotonin and melatonin. A small share becomes serotonin, in the gut and in the brain¹. The step in between is 5-hydroxytryptophan, sold as the supplement 5-HTP⁴, and the pineal gland turns serotonin into melatonin, the hormone that rises at night⁵.
• The kynurenine pathway. This route handles roughly 95% of tryptophan breakdown, about 90% of it in the liver. Its products include NAD⁺, the coenzyme cells use to produce energy, and nicotinic acid, a form of vitamin B3².

That last link is why tryptophan counts toward your niacin intake. The US Food and Nutrition Board defines one milligram of niacin equivalents as 1 mg of niacin or 60 mg of tryptophan. How efficiently people make that conversion varies, and it depends on riboflavin, vitamin B6 and iron⁶. For the energy side of the pathway, see NAD+ restoration.

The kynurenine pathway has two possible first steps. In the liver, tryptophan 2,3-dioxygenase (TDO) disposes of excess tryptophan. Everywhere else the gatekeeper is IDO, which answers to interferon-gamma and other inflammatory signals². Because the same tryptophan supply feeds both pathways, how active IDO and TDO are also affects how much is left for serotonin⁴.

IDO was first understood as a weapon against infection. In a 1984 laboratory study, interferon-gamma, a signalling protein released by activated immune cells, stopped the parasite Toxoplasma gondii from growing inside human cells. It did so by making the cells break down their own tryptophan, which the parasite needs. Two other interferons, alpha and beta, did not trigger this breakdown⁷.

Later work confirmed that interferon-gamma switches on IDO and that starving microbes of tryptophan also restrains other organisms that live inside cells, such as Chlamydia trachomatis. Raised kynurenine levels have been found in people with a range of diseases and after interferon treatment⁸. So IDO is part of normal immune defence: a way of denying invaders a nutrient they cannot make themselves.

The discovery that changed the field came from pregnancy. A fetus carries the father's genes, so to the mother's immune system it is partly foreign tissue, yet it is not rejected. In 1998, Munn and colleagues gave pregnant mice a drug that blocks IDO, and T cells rapidly rejected every fetus that carried the father's tissue type. By breaking down tryptophan, the pregnancy suppresses T cells and protects itself⁹.

Research since then has described at least three ways IDO holds T cells back:

• Starvation sensing. T cells monitor their amino acid supply through a stress-sensing enzyme called GCN2. When IDO-expressing dendritic cells drain the local tryptophan, GCN2 switches on, and the T cells stop dividing and become unresponsive, a state called anergy. In mice, T cells lacking GCN2 were not suppressed¹⁰.
• Toxic breakdown products. Kynurenine and related metabolites, including 3-hydroxykynurenine, 3-hydroxyanthranilic acid and picolinic acid, inhibit T cells and natural killer cells and, with longer exposure, kill them. The effect falls mainly on cells that are being activated, while resting cells are largely spared^{11, 12}.
• Making regulatory T cells. Kynurenine activates the aryl hydrocarbon receptor (AhR), a sensor inside cells, and in mouse T cells this produced FoxP3⁺ regulatory T cells, the immune system's peacekeepers¹³. In another mouse study, tryptophan starvation plus kynurenines turned naive T cells into regulatory cells that could hold back the T cells that cause autoimmune diabetes¹⁴.

The overall effect is a shift from attack toward tolerance, which the body needs in some places and not in others. A 2004 review drew together evidence for this role in pregnancy, tumour resistance, chronic infections and autoimmune disease³. For the wider picture of how T cells are supported and kept in check, see our pages on T-cell function and cytokine balance, and our immune system hub.

The gut. The intestine is where the immune system meets the most foreign material, and tryptophan is central to keeping that meeting calm. Gut bacteria steer three tryptophan routes there: serotonin, kynurenine and a family of microbial indoles¹⁵. In mice, Lactobacillus bacteria that feed on tryptophan produce indole-3-aldehyde, which activates AhR and the barrier-protecting signal interleukin-22. That kept the fungus Candida albicans in check and protected the gut lining from inflammation¹⁶. This is part of the reasoning behind interest in probiotics and the gut microbiome for mucosal immunity and gut barrier integrity, but it is a mouse finding, not evidence that a particular probiotic works this way in people.

Inflammatory bowel disease. In 535 people with inflammatory bowel disease (IBD), blood tryptophan was lower than in 291 matched people without IBD, more so in Crohn's disease than in ulcerative colitis. Lower tryptophan went with more active disease and higher C-reactive protein, the IDO1 gene was more active in colon biopsies, and kynurenine-pathway products such as quinolinic acid were high. The authors called for trials to test whether changing tryptophan pathways affects IBD severity¹⁷.

Autoimmunity. Regulatory T cells created by tryptophan breakdown restrained autoimmune diabetes in mice¹⁴, and researchers count IDO among the body's checks on autoimmune disease³. Whether strengthening this brake helps people with rheumatoid arthritis, multiple sclerosis, lupus or other autoimmune conditions has not been established. Our autoimmune health hub and autoimmune modulation page cover the supplements that have been tested.

Cancer. Tumours need to escape T cells, and many use the same trick as a pregnancy. A 2003 study reported that most human tumours express IDO. In mice, tumour cells made to express IDO escaped rejection by immunised animals, tumour specific T cells failed to gather at the tumour, and an IDO-blocking drug partly reversed this¹⁸. Some human brain tumours use the liver enzyme TDO instead: the kynurenine they make activates AhR, suppresses anti-tumour immunity and is associated with faster progression and poorer survival¹⁹.

That made IDO an attractive drug target. Early trials combining IDO1 blockers with immunotherapy looked promising, but the phase 3 ECHO-301/KEYNOTE-252 trial in 706 people with advanced melanoma found no benefit. Median progression-free survival was 4.7 months with the IDO1 inhibitor epacadostat plus pembrolizumab and 4.9 months with placebo plus pembrolizumab (hazard ratio 1.00), and overall survival did not differ either²⁰. The pathway is still being studied as a drug target in cancer, neurodegeneration and other diseases²¹. Our cancer page covers the supplement evidence for people living with cancer.

Chronic infection. In people with HIV, progressive disease was linked to a loss of Th17 cells, which help guard the gut barrier, and a matching rise in regulatory T cells, in blood and in gut tissue. This went along with IDO1 switched on in dendritic cells and more bacterial products in the blood, and in the laboratory the IDO product 3-hydroxyanthranilic acid tipped the same balance. The authors proposed that IDO helps keep the chronic inflammation of HIV going²².

IDO also links chronic inflammation to the brain. In 16 people with cancer treated with interleukin-2, interferon-alpha or both, blood tryptophan fell over the first month of therapy. The larger the fall, the more depressive symptoms they developed, including pessimistic thoughts, loss of concentration and suicidal thoughts²³.

Animal work suggests IDO is a cause rather than a bystander. In mice, a bacterial toxin that triggers inflammation (lipopolysaccharide) switched on IDO and produced depression-like behaviour. Blocking IDO, directly or by damping the inflammation, prevented it and normalised the kynurenine-to-tryptophan ratio in blood and brain, and giving kynurenine alone produced the same behaviour²⁴. Several kynurenine-pathway products act on the brain, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid, and imbalances in the pathway have been associated with depression, schizophrenia and neurodegenerative disease²⁵.

Exercise may steer the pathway in a protective direction. In mice, the muscle program that endurance training switches on (PGC-1α1) raised the enzymes that turn kynurenine into kynurenic acid, which cannot cross into the brain, and mice engineered to have more of that program in muscle resisted stress-induced depression²⁶. These are mouse findings. For what has been tested in people, see depression, depression symptom reduction, brain inflammation reduction and our mental health hub.

A handful of small human trials have measured kynurenine-pathway markers after a supplement. Their results are mixed, and none has shown that changing the pathway improves how T cells work or how well people fight infection.

• Omega-3: 4 g a day for 12 weeks in 47 healthy men lowered some inflammatory markers but did not change kynurenine metabolites, depressive symptoms or mood²⁷.
• Vitamin D: 5,000 IU a day with phenylbutyrate for 16 weeks in 167 people with untreated HIV did not change the kynurenine-to-tryptophan ratio²⁸. A single 150,000 IU dose before an ultramarathon blunted the post-race rise in several kynurenine metabolites in 35 amateur runners²⁹.
• Ellagic acid: 180 mg a day for 12 weeks in 50 people with multiple sclerosis and mild to moderate depressive symptoms lowered IDO gene expression, interferon-gamma and depression scores. It is a single small trial³⁰.
• Curcumin: in mouse immune cells, curcumin, the active compound in turmeric, stopped interferon-gamma from switching on IDO and reversed IDO's suppression of T cells³¹. That is a laboratory experiment; it has not been shown in people taking curcumin. Because IDO also calms inflammation, blocking it is not automatically a good thing.

L-tryptophan itself. In a crossover trial in 20 healthy volunteers, 3 g a day for three weeks was well tolerated and raised kynurenines and AhR activity in the small intestine, but it did not change cytokine production by immune cells³². Its clearest benefit is for sleep: a 2022 meta-analysis found that tryptophan shortened time spent awake after first falling asleep, more so at 1 g a day or more, though it did not change other sleep measures³³ (our summary; see also insomnia). For depression, a Cochrane review found only two small trials, with 64 patients, good enough to include. They favoured tryptophan or 5-HTP over placebo, but the evidence was too weak to be conclusive³⁴ (our summary). Claims that tryptophan supplements "support immunity" go beyond this evidence.

Vitamin B6 and niacin. The kynurenine pathway depends on pyridoxal 5'-phosphate, the active form of vitamin B6. Its blood level is consistently low during inflammation, and B6 improves some immune functions in people and animals who are deficient in it³⁵. Riboflavin, B6 and iron are also needed to turn tryptophan into niacin⁶. Correcting a deficiency makes sense; it has not been shown that extra B6 or niacin changes IDO activity in people who are not deficient.

Eosinophilia-myalgia syndrome. In 1989, an outbreak of eosinophilia-myalgia syndrome, an illness of muscle pain and high eosinophil counts that can leave lasting nerve and skin damage, was traced to tryptophan supplements. Of affected people whose supplement source was known, 29 of 30 had used tryptophan from a single manufacturer, compared with 21 of 35 controls, and the illness was linked to a chemical impurity tied to that company's manufacturing conditions³⁶. The US Food and Drug Administration banned tryptophan sales, cases fell rapidly, and the ban was lifted in 2005; a new tryptophan-linked case was reported in 2011³⁷ (our summary).

Serotonin syndrome. This potentially life-threatening reaction to excess serotonin activity is classically caused by combining serotonergic drugs with monoamine oxidase inhibitors (MAOIs)³⁸. The first description of it, in 1960, involved L-tryptophan given with an MAOI, and clinicians assessing the syndrome are advised to ask about supplements including tryptophan³⁹. If you take an antidepressant or another serotonergic medicine, check with your prescriber before adding tryptophan or 5-HTP.

• IDO is part of normal immune regulation, not a defect. It helps protect a pregnancy and keeps T-cell responses in check^{9, 3}.
• Inflammation is what switches it on², so the most direct lever is dealing with the source of chronic inflammation, with your clinician where there is an underlying condition. Our inflammation hub collects the supplement evidence.
• Blocking IDO is not a proven strategy: the largest trial of an IDO1 drug, in melanoma, showed no benefit²⁰.
• Supplements that touch this pathway, such as L-tryptophan, 5-HTP, vitamin B6 and curcumin, each have their own evidence pages. None has been shown to tune IDO in a way that improves immune health.

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