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If you are having a hard time reading the material, then just read the bolded parts.

Introduction to T Regulatory Cells (Tregs)

Tregs comprise ∼5%–10% of T helper cells and can be identified by the DNA reading protein ‘Foxp3’ or a lot of CD25 proteins on its membrane/surface.

There are two types of Tregs: ‘natural’ (nTregs) or ‘induced’ (iTregs). Both types are anti-inflammatory. Natural means that they are part of the cells naturally found in our thymus gland. Induced means that they are created outside the thymus. (There are 2 kinds of induced Tregs: Tr1 and Th3) (R, R2).

Tregs produce TGF-B and interleukin IL-10, both of which mostly inhibit the immune system (R).

Tregs suppress the harmful/activated (effector) Th1, Th2, Th17 cells and their cytokines, eosinophils, mast cells, basophils, IgE’s (switches to IgG4) and the migration of inflammatory cells to tissues (R).

In addition,  they suppress CD8+ T cells, dendritic cells (DCs), monocytes/macrophages, B cells, natural killer cells and natural killer T cells (R).

Tregs need to be ‘activated’ in order to have their suppressor functions (R).

Tregs inhibit immune activation by a direct cell to cell contact. This means that it doesn’t only work through cytokine intermediaries such as TGF-B and IL-10These cells are directly anti-inflammatory (R). For some reason, this information excites me.

Top 8 Picks to Increase Tregs

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The Good

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Treg cells help to restrain the immune system and prevent an excessive T Cell response (R).

Even is healthy people, immune cells can attack our own tissue. Tregs stop our immune cells from attacking our own tissue (R).

In particular, TGFb and IL-10 seem to be crucial for sustained tolerance induction by Treg. (R)  On the other hand, TNF, IL-1 and IL-6 block the ability of Tregs to induce tolerance (R).

Tregs can also reverse food intolerances and allergies.

Probably the single most important reason we develop IgE-related allergies is because we aren’t creating Treg cells in the gut, but instead Th2 or Th17 cells (R).

This happens in 3 ways: by changing the type of dendritic cells that reside in our gut, by blocking Th2/mast cells/other immune cells, and by actually changing the tissue structure of our gut (R).

Our gut has dendritic cells that capture proteins from food and bring them to the lymph nodes. To produce Tregs, we need sufficient vitamin A, TGF-B, and the enzyme IDO (R).

If we produce Tregs, then they will tell the dendritic cells that the protein they carry is cool and there’s no need to ring the alarm bells (R).  

For oral tolerance, immune cells (DCs) are told not to react to a protein in the gut tissue, and these cells circulate to other tissues, which trains the immune system (R).

Technical: Tregs produce inhibitory cytokines (eg, IL-10, TGFb, and IL-35), absorb inflammatory cytokines, kill target cells directly (secretion of granzymes, perforin), block important cellular functions (through CD25, 39, 73 and adenosine), increase cAMP (and therefore energy), decrease costimulatory molecules (CD80/CD86) and turn the dendritic cells off by activating surface proteins that inhibit immune function (CTLA-4, PD-1, or Histamine Receptor 2 ) (R, R2).

I’ve tried all different ways to induce tolerance, but I haven’t found this to be effective for lectin sensitivity at all. This works for probably most other food allergies.

Treg cells, surprisingly, can be important for clearing some infections. They are crucial for the establishment of a functional Th17 response after the infection in the gut (with the help of IL-2) (R).

Tregs can improve wound healing (R) and are neuroprotective in stroke models (R).

The Bottom Line: If you’ve got autoimmune or inflammatory problems, there’s a good chance that you’re deficient in Tregs or that they’re dysfunctional.  Tregs can then be considered ‘good’.

The Bad

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Unrestrained Treg-cell activity can lead to impaired immunity (R), which means high Tregs will make you will be less capable of fighting most infections.

For example, a high level of Tregs can theoretically make people with CFS and other disorders believed to be caused by viral infections worse.  Indeed, not surprisingly, people with  CFS have higher levels of Tregs. (R)

In my EBV/Mono post, I speak about how various autoimmune disorders can be caused by a viral infection that’s out of control.

Two significant factors that cause this is a low Th1 immune system/low INFy and low cytotoxic T cells (CD8+).

If you have high Tregs, it will decrease both of these immune system aspects, plus others that are involved with keeping viral infections at bay.

So any disorder caused or aggravated by a viral infection should become worse by having high Tregs. 

However, if you have high Tregs, it will create tolerance to specific tissues and will, therefore, be overall beneficial when it comes to classical autoimmune disease. And we see this below in the list of diseases with low Tregs.

This may not be the case for something like CFS, though, which is more systemic rather than a specific tissue being attacked as is the case by a classical autoimmune disorder.

Tregs can have a dark side when it comes to cancer because they limit our ability to fight tumors, to a degree.  They curtail the generation of Th1 responses.  Part of these responses is the production of CD8+/Cytotoxic T cells and IFNy. Both of these fight tumors (R).

Tregs are also the main source of IL-10 in tumors, which I discussed inhibits our ability to kill tumors to some degree (R).

Tregs also inhibit the body’s ability to suppress the formation of cancerous cells (R), which means high Tregs will lead to cancer.

Patients with tumors have a local excess of Tregs (R).

Tregs can also increase inflammation in certain situations because they can become dysfunctional and start producing IL-17 (R).

Bottom Line: If you’ve got cancer, you might want to shift your immune system to decrease Tregs – at least in cancer tissue. However, systemic levels do likely influence levels in cancer tissues.

The Ideal Treg Scenario

The ideal scenario is to have a healthy Treg level throughout your body, but low Treg levels in cancer or precancerous tissue.  

Also, ideally, Tregs would be decreased when we have an infection and increase when we get over it.

Why Can’t We Just Inject Tregs Into People?

Unfortunately, recent T cell biology investigations revealed that T cell nature is much more plastic than initially thought (R).

Treg cell therapy may be very risky, as the Treg cells transferred to the patient may reverse and become another proinflammatory Th17 cell (R). IL-10 is a cytokine that blocks this conversion from happening (R).

You see, in these cells, there are two proteins that read the DNA, which command the cell’s activities and produce products: Foxp3 and RORyt. When Foxp3 decreases relative to RORyt, the cell will start producing more IL-17.  There’s no dividing line at which Tregs become dark villains; it’s on a continuum (R).

So it’s the level of Foxp3 in the Treg that matters most.  In psoriasis, skin cells have lots of Tregs but reduced Foxp3 (R).

The good news is that HDAC inhibitors such as Butyrate block the conversion of healthy Tregs to IL-17 producing Tregs (R).

Tregs are produced under the influence of solely TGF-β. Th17 cells are produced under the influence of TGF-β AND IL-6 or IL-21 (human studies point to IL-21, while mouse studies point to IL-6) (R).

Various cytokines such as IL-1b, IL-2 (Th1 cytokine), IL-23 and IL-15 turn Angelic Tregs to Villain Tregs.

What needs to be done then to heal yourself/prevent disease is to change the environment of these cells. This means to decrease systemic inflammation, ideally by getting to the root cause.

Diseases With Low/Dysfunctional Tregs

  • Heart Disease/Atherosclerosis (R)
  • IBS (R)
  • Diabetes (R)
  • Sleep apnea (R)
  • Allergies (RR2)
  • IBD (R): Colitis (R), Crohn‘s (R).
  • Rheumatoid arthritis (R) – The function of Treg is known to be suppressed by TNF-α in RA (R)
  • Multiple sclerosis (R), Type I diabetes (R), SLE (R)
  • Hashimoto’s (R), Graves (R) – Dysfunctional Tregs, not lower numbers… In Thyroiditis patients, two studies showed no deficit in Treg number, while another study found that only untreated Graves’ patients had a significant decrease in Tregs (R).
  • Eczema (R), Psoriasis (R).
  • Gastritis, oophoritis, Prostatitis, Renal disease (R).

Increasing Tregs

Increasing Tregs is a way to benefit both Th1 and Th2 dominance (R). Tregs decrease Th1 cells and help create oral tolerance for Th1/Th2 type allergies.

Inhibiting mTOR results in increased Treg levels (R).

However, studies have found that having variations in mTOR is important for Treg development. So you don’t want to constantly inhibit it; instead, cycle with high and low mTOR activation (R).

The depletion of arginine, glutamine, and tryptophan increases Treg generation (via inhibiting mTOR) (R).

Increasing AMPK also increases Tregs (mTOR article has AMPK activators) (R).

Tregs prefer to burn fat for fuel and when you take this away from them, they are less likely to develop (R).

Oddly, gluten may increase Tregs. Tregs were significantly lower in patients who had abstained from gluten compared with individuals on a standard diet (R). However, I wouldn’t pay much attention to this, because Tregs probably went down as a result of less inflammation (so there needed to be less Tregs)…

Decreasing Tregs

The mTORAkt pathway suppresses Treg cell production and activity (R). So you want to inhibit mTOR.

Contradictory/Doesn’t Alter Tregs

Unknown

Stevia, Blueberry

Oxidative Stress Helps Tolerance…What To Do?

Oxidative stress/ROS actually helps Tregs suppress immune activation. Particularly, NADPH oxidase is important (produces superoxide). In fact, Tregs are able to suppress the secretion of cysteine into the microenvironment by dendritic cells to indirectly suppress T effector proliferation via cysteine depletion (R).

First, there’s no need to worry about molecular hydrogen because that doesn’t affect the free radical superoxide, which is what the study is concerned with.

However, this puts a damper on NAC and Spirulina, both of which inhibit the oxidant in question.

However, I’ve done well on NAC and most clients report positive results.

In addition, many benefits have been reported in a clinical trial: NAC increased mitochondrial membrane potential in all T cells, profoundly reduced mTOR activity, enhanced apoptosis, reversed expansion of CD4−CD8− T cells, stimulated FoxP3 expression in CD4+CD25+ T cells, and reduced anti-DNA production (R). Increased mitochondrial membrane potential leads to the destruction of activated T cells (R).

I think what might be happening here is NAC may briefly decrease the induction of tolerance for a couple of hours. Since it’s brief, it’s not an issue. Otherwise, NAC may behave differently when people ingest it. Whatever the case, I think the benefits outweigh this potential negative.

Disclaimer and Caveats

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The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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22 COMMENTS

  • whisperingsage

    Read the whole blog and get him tested, the price here is very reasonable. I’m going to be doing that soon. I’m on a lot of what he recommends by my own research, but he provides a lot more clues. Getting my self tested is going to be a solution as insurance us so impossibly high and the docs don’t delve this deep into my concerns.
    So 1. You have to take responsibility for getting yourself educated and not rely on someone else to do that. If you are motivated, you WILL do that. Don’t forget, the docs were not born with knowledge, they had to learn it and in my not so humble opinion, most have not done a very good job. Most have forgotten basic physiology. And ruined many lives with that ignorance.

  • Amit shah

    My son has severe asthma may be th17 plus th2 can you guide what best possible way to heal

  • Jamie

    Hey, Yeah the studies I have read are majorly complex and conflicting.. I have reduced my intake of the supplement to just one capsule a day after going a week completely without the fish oil which equates to 504mg EPA and 378mg DHA so I’ll see how it goes as I was on this amount for roughly a year without any ill effects.. It was when I started taken one capsule morning and night after a few month I discovered the alopecia areata on my beard and also thinking back I got tonsilitas pretty bad for a couple of week so maybe with my immune system already compromised that caused the onset of alopecia.. haha there are a dozen theories running around my head.. I even thought it could have been caused by creatine monohydrate as I also took that before noticing the paych in my beard.. that too apparently effects the immune system.. with all these theories I am still pretty sure it’s excess fish oil that is to blame as I had my first bowt of alopecia areata shortly after mega dosing 3 capsules a day back in 2015, experienced full re growth on that patch a yeat after. Moderation is probably key.. DHA is in alot of foods surprisingly.

  • John S

    So what did you end up doing? Did you stop taking DHA? On one hand, the ratio of omega 6:3 is important to control autoimmunity. On the other hand, DHA may impair Tregs. I found the study you mentioned. It seems like while it does impair Tregs, it does increase some expressions that are useful for Tregs too. It’s all very complex… and gives you a dilemma on whether DHA is useful or not.

  • John S

    Add naringenin to the list of items that increases Tregs.

    http://pubs.acs.org/doi/abs/10.1021/jf204625y

  • Jamie

    DHA reduces suppressive and migratory effects of tregs according to a ncbi study I found so surely this can’t be good promoting tregs?
    Tregs have recently been found to potentially play a beneficial role in people who suffer Alopecia Areata. I myself suffer from the disorder with patches on my facial hair. I have a strong feeling it could be down to increasing my omega3 fish oil supplementation.. 2 capsules a day amounting to around 1000mg EPA & 700 DHA.

    This is a section of the study I found..

    The suppressive capacity of Treg cells depends on their ability to migrate and enter the tissues, and this might help prevent autoimmune disease progression (9). This trafficking ability of Treg cells depends on their capacity to express migratory and adhesion factors. By analyzing the expression of the chemokine receptors (needed for their migratory ability), we observed that Treg cells expressed higher CCR-4, CCR-8, and CXCR-4 mRNA than Teff cells as it has been reported in previous studies in mice (9) and human (25). As far as DHA is concerned, we observed that the exposure of Treg cells to DHA significantly reduced their ability to migrate toward MDC and SDF-1. In an attempt to link the expression of the chemokine receptors, we observed that DHA curtailed the expression of CCR-4 and CXCR-4 mRNA in Treg cells. It is noteworthy that DHA did not affect the migration of Teff cells, and this observation is in accordance with a study that has shown that some agents, like dopamine, only affected the migration of Treg cells without influencing the same in Teff cells (9). Since Treg cells highly express L-selectin, which is essential for their migration and normal tissue distribution (38), it is possible that DHA is inhibiting their migration via inhibition of expression of L-selectin. Indeed, we noticed that DHA curtailed significantly the expression of L-selectin mRNA in Treg cells. These observations again explain the diminished migration of Treg cells even in the absence of MDC and SDF-1. Our observations corroborate the report of Collie-Duguid and Wahle (39) who have shown that both DHA and EPA transcriptionally decrease the expression of adhesion molecules, such as P-selectin and ICAM-1, induced by cytokines in several cell lines. As anticipated, the Teff cells did not express L-selectin mRNA in high quantities and DHA did not affect the same

  • maddy

    For the Hashimoto’s try Selenium. This should reduce the antibodies. On the hair loss, that is definitely autoimmune condition. does she have any food intolerances or food allergies? You may want to try bovine colostrum and sodium butyrate. Both of these heal the gut, work against gut infections and boost immune tolerance. it takes TIME with these. A few months. but take them faithfully. totally reversed my daughter’s food allergies this way, and we were carrying an epi-pen. Acetyl-glutathione will boost internal cellular glutathione. glutathione is needed for the enzymes inside the cell which turn T4 into active T3. you may want to try this too. but probably one at a time…

  • Flelcia

    What is NAC. My 11 yr old daughter has ALopecia areata. I give her probiotics and d3, does not help w hair growth so far. She also has hashimoto.

  • julialoha

    Decreasing Tregs

    The mTOR–Akt pathway suppresses Treg cell production and activity (R). So you want to inhibit mTOR.

    High-fat diet (R) (in mouse livers)
    Leptin (R)
    Marathons/Excess exercise (R)
    Artemisinin (R) – in cancer cells
    NAD+? (R)
    Melatonin (R) – in tumor tissues

    So do I want high fat diet, lots of leptin, plenty marathons, artemisinin for my cancers and More melatonin for my tumor’s benefit?????? or is this the list of things to avoid if my tregs are too high and I want to reduce them?

    The part about increasing Tregs made good sense to me in that I thought increasing all those things listed was the right thing to do. Yes?

    apologizing to all those who find my confusion simpleminded.

  • Chantel Jones

    Again, SIR, thank you for such for this CLARITY and getting right to it style of sharing information. You are brilliant! Thanks so much for sharing! Kind regards CJ

  • Tim Rees

    great article, thanks a lot

  • thomas ichim

    awesome post !! im really happy to find someone that writes REAL STUFF on the internet !! keep up the great work

  • Remy

    Also, I have been taking the Swanson probiotic mentioned above but am curious what it is about that probiotic that makes it unique? From the linked article, it seems like many probiotics have those common strains. What have I missed, please?

  • Remy

    I had the T cell activation panel at Labcorp which includes the CD3CD25 cells…are you saying that if the absolute number of these cells is high, that is a sign of autoimmunity?

    Do you think this Mayo test panel would be more useful?

    http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/89318

    Thanks!

  • Alex

    What should one do if they have a high level of TGF-B1? Over the reference range. Also, a low level of VEGF. How are these two related?

    1. Joseph M. Cohen

      You got that tested bec mold problems?

  • Joanna

    http://www.nature.com/nm/journal/v20/n11/full/nm.3704.html

    inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3+ regulatory T (Treg) cells.

    ____

    I have reason to think that I will develop an autoimmune condition in my lifetime. I’m referencing your post at the moment. Thanks for taking the time to put it together.

    1. Joseph M. Cohen

      🙂

    2. Rhonda Else

      Can you explain this? So what is a person to do to prevent autoimmune disease using this theory? Thanks.

      1. David Sander

        For auto immune problems, consider raising vitamin D3 to high normal of 70-100 NGOs/ml in blood or follow the Dr Coimba protocol for MS with your doctors of very high vitamin D doses, add 5000–15,000 IU of vitamin A in the Retinol form, take Boron in a 15 to 45 mg dose as suggested by Dr Jorge Fletchas MD in his videos for arthritis. Add in a good DHA dose from fish oil, reduce your omega-6 in manufactured vegetable oils that oppose the omega-3 oils, add in curcumin. Change your diet to a LCHF type or paleo and possibly add a whey protein supplement and the arginine, glutamine, and ??? Amino acids. Exercise regularly and afterward eat a good recovery meal with some carbs, but marathon training should not be required
        Look over the list again for items you can include like alpha lipoid acid.

        1. David Sander

          The NGOS is 70 to 100 ng/ml in blood testing.

  • lordLord

    awesome .

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