Regulating T Cells

Our immune systems are heavily invested in the generation of immune tolerance (Immune tolerance is known as the state of an active, highly regulated unresponsiveness of the immune system to self-antigens or against a particular antigen that can induce an immune response in the body), and nowhere is this more concentrated than in our gastro-intestinal tract. Here the immune system faces a unique mix of an ever-changing array of food antigens and a large and complex concoction of micro-organisms. The gene products of these also provide essential support for nutrient production, detoxification, and other necessary metabolites.

It is at this interface that the boundaries of self and non-self are at their most fuzzy.

Whilst physical boundaries provided by the mucus layers and the epithelial tight junctions provide part of this separation, a key mediator in this milieu is found in the role provided by specialist T cells called Regulatory T cells. Their primary role is to regulate mucosal immunity to food antigens, damage-associated self-antigens, and commensal and pathogenic microorganisms via anti-inflammatory cytokines and small molecules that are used to moderate many immune cells, IgA production and barrier repairs[1]. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs[2].

These Treg cells are also able to migrate and help promote tissue regeneration in skeletal tissue and the liver making them powerful allies in the generation and management of health[3].

Whilst current understanding recognises a small range of Treg cells, it is the family developed and found in the mucosal wet tissues that have the greatest impact on our health. Therefore, understanding how to preserve and enhance their development and circulatory benefits makes for an attractive health generation proposition.

Treg cells are essential not only to control misguided immune responses and to maintain self-tolerance but also to avoid excessive immune reactions[4]. Stimulating Tregs by emulating or enhancing natural mechanisms makes for a promising therapeutic strategy.

The most suitable sites for promoting the expansion of Tregs are mucosal tissues, particularly the intestinal mucosa, as they have embedded inductive mechanisms that enable the differentiation of antigen-specific peripheral Tregs (pTregs) required to maintain tolerance to environmental agents such as the microbiota and food antigens.

Interestingly, naturally induced pTregs at the gut mucosa can also provide systemic bystander immunosuppression conferring immune tolerance to distant tissues.

SCFAs

The gut microbiota can promote the induction of Tregs through the production of Short-Chain Fatty Acids (SCFAs) derived from microbial fermentation of dietary fibre such as that found in the following foods[5].

Whole Grains: Foods like whole wheat (excluded from gluten-reactive individuals), oats, brown rice, quinoa, and barley (excluded from gluten-reactive individuals) are high in dietary fibre, which serves as a substrate for SCFA production in the gut. Consuming these whole grains can support the growth of beneficial gut bacteria and the production of SCFAs like butyrate.

Legumes: Beans, lentils, chickpeas, and other legumes are excellent sources of dietary fibre. They can provide fermentable substrates for gut bacteria, leading to increased SCFA production, including butyrate. Incorporating legumes into your diet can support Treg induction.

Fruits and Vegetables: Many fruits and vegetables contain soluble fibre, which can be fermented by gut bacteria to produce SCFAs. Examples include apples, bananas, berries, broccoli, Brussels sprouts, carrots, and sweet potatoes. Including a variety of fruits and vegetables in your diet can help promote SCFA production and Treg induction.

Fermented Foods: Fermented foods like yoghurt, kefir, sauerkraut, kimchi, and pickles contain live beneficial bacteria. These bacteria can contribute to the fermentation of dietary fibres and the production of SCFAs. Consuming fermented foods may help support a healthy gut microbiota and Treg development.

Nuts and Seeds: Almonds, walnuts, chia seeds, flaxseeds, and other nuts and seeds are good sources of dietary fibre. They can contribute to SCFA production when fermented by gut bacteria. Including a variety of nuts and seeds in your diet can provide fermentable substrates and promote Treg induction.

Probiotics

There is also evidence that the composition of the microbiota can affect Treg number and function[6]. Probiotics containing species belonging to the genera Clostridia, Lactobacilli and Bifidobacterium, and Bacteroides fragilis can increase the population of Tregs in the colon of germ-free animals. Probiotics exert their immunomodulatory effects through a multifaceted interplay with the host’s immune system. Several mechanisms have been proposed for the induction and expansion of Tregs by probiotics. However, the duration of such treatments is unclear, as the existing microbiota is largely stable over time and quite resistant to modification.

Micronutrients

While the induction of Tregs is a complex process influenced by various factors, including genetic and environmental factors, several micronutrients have been identified as important for promoting Treg development and function. Here are some key micronutrients involved in the induction of Tregs in the gastrointestinal tract of humans:

Vitamin A: Vitamin A and its metabolites, such as retinoic acid, have been shown to enhance Treg development and function in the gut. Retinoic acid promotes the expression of gut-homing receptors on Tregs, allowing them to migrate to the intestinal mucosa and exert their suppressive effects[7]

Vitamin D: Vitamin D has immunomodulatory properties and is involved in promoting Treg differentiation and function. It enhances the expression of the transcription factor Foxp3, which is critical for Treg development[8].

Omega-3 fatty acids: Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), possess anti-inflammatory properties and have been shown to increase Treg numbers and function in the gut. They can modulate various immune signalling pathways involved in Treg induction[9].

Zinc: Zinc is an essential micronutrient involved in numerous immune processes. It has been shown to promote Treg differentiation and function, as well as maintain their stability. Zinc deficiency may impair Treg development and compromise immune tolerance[10].

Selenium: Selenium is a trace element that exerts antioxidant and anti-inflammatory effects. It has been shown to enhance Treg numbers and function in the gastrointestinal tract. Selenium deficiency can negatively impact Treg induction and compromise immune regulation[11].

Comment

It’s important to note that the process of Treg induction is complex, and the interactions between various micronutrients and immune cells are still being studied. Additionally, individual variations and specific health conditions may influence the effectiveness of these nutrients in Treg induction. It is always advisable to consult with a healthcare professional or registered nutritional therapist for personalised food and supplement recommendations.

References:

[1] Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol. 2021 Aug 4;12:716499.

[2] Fiyouzi T, Pelaez-Prestel HF, Reyes-Manzanas R, Lafuente EM, Reche PA. Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases. Int J Mol Sci. 2023 Apr 25;24(9):7797

[3] Hanna BS, Wang G, Galván-Peña S, Mann AO, Ramirez RN, Muñoz-Rojas AR, Smith K, Wan M, Benoist C, Mathis D. The gut microbiota promotes distal tissue regeneration via RORγ⁺ regulatory T cell emissaries. Immunity. 2023 Apr 11;56(4):829-846.e8.

[4] Eggenhuizen PJ, Ng BH, Ooi JD. Treg Enhancing Therapies to Treat Autoimmune Diseases. Int J Mol Sci. 2020 Sep 23;21(19):7015.

[5] Tan J, Taitz J, Sun SM, Langford L, Ni D, Macia L. Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development. Front Nutr. 2022 Apr 20;9:878382.

[6] Kamada N, Núñez G. Role of the gut microbiota in the development and function of lymphoid cells. J Immunol. 2013 Feb 15;190(4):1389-95.

[7] Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007 Jul 13;317(5835):256-60.

[8] Fisher SA, Rahimzadeh M, Brierley C, Gration B, Doree C, Kimber CE, Plaza Cajide A, Lamikanra AA, Roberts DJ. The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A systematic review. PLoS One. 2019 Sep 24;14(9):e0222313.

[9] Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010 Sep 3;142(5):687-98

[10] George MM, Subramanian Vignesh K, Landero Figueroa JA, Caruso JA, Deepe GS Jr. Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance. J Immunol. 2016 Sep 1;197(5):1864-76.

[11] Hu Y, Feng W, Chen H, Shi H, Jiang L, Zheng X, Liu X, Zhang W, Ge Y, Liu Y, Cui D. Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto’s thyroiditis: A prospective randomized-controlled trial. Clin Transl Sci. 2021 Jul;14(4):1390-1402.