What are regulatory T lymphocytes (Treg)?

Regulatory T lymphocytes (Treg) are one of the subpopulations of T lymphocytes that play a key role in maintaining peripheral tolerance, in preventing autoimmunity and in limiting chronic inflammatory diseases. However, Treg also limit beneficial immune responses by suppressing protective immunity against pathogenic microbes or immune response to tumors.

The vital role of the immune system is to protect the organism from pathogenic microbes and harmful substances.  It has the ability to distinguish self vs. foreign antigens and not to react to antigens of its own cells and tissues. The key questions in immunology and medicine is how to maintain immune tolerance and how to control aberrant or excessive immune responses in autoimmune and chronic inflammatory diseases.

Nowadays, we know that Treg are actively involved in maintaining immune tolerance and homeostasis.

1. Discovery of Treg

The ability of T cells to suppress the immune response was first described in the 1970s, but it was not until the 1990s that Sakaguchi introduced the concept of regulatory T lymphocytes (Treg) and described their phenotype. Studies of Treg-specific molecular markers have shown that Treg are CD4+ T cells and constitutively express the alpha-chain of the interleukin-2 receptor (IL-2R), CD25. Removal of CD25+ CD4+ Treg resulted in the development of a spectrum of autoimmune diseases in experimental animals. This was a direct evidence that Treg maintained immune tolerance and that their dysfunction or deficiency could be a cause of autoimmune diseases. It was later discovered that Treg specifically expressed the transcription factor Foxp3. Treg has been shown to play a crucial role in human immune tolerance because mutations in the Foxp3 gene impair  development/function of Treg and cause genetic diseases in humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by autoimmune diseases such as diabetes type 1 and thyroiditis, inflammatory bowel disease and allergies.

These studies provided solid evidence that Foxp3+ CD25+ CD4+ Treg are indispensable for establishing and maintaining immune tolerance and preventing autoimmunity.

Nowadays Treg cells have clinical use and are used for treatment and prevention in autoimmune diseases, tumors, organ transplantation and allergies.

2. Foxp3: the main regulator of Treg

Stable Foxp3 expression is the dominant regulatory factor for Treg development and function. The key role of Foxp3 in regulating immune tolerance has been demonstrated by the development of lethal autoimmunity in Foxp3 deficiency in “scurfy” mice. Mutations in the Foxp3 gene are the cause of IPEX disease in humans, which is characterized by widespread autoimmunity in multiple organs, and most patients die before the age of three, unless treated with a bone marrow transplant. More than 75 different mutations of the Foxp3 gene have been defined in patients with IPEX. Most patients with IPEX do not have Treg cells or there is a significant impairment of their function.

Foxp3 is localized in the nucleus and binds to over 700 genes involved in a variety of cellular functions, including T cell receptor signaling, cellular communication and transcription regulation. A number of other transcription factors have been discovered that interact with Foxp3 and thus shape certain Treg functions, such as Runk1, NFAT, Eos, IRF-4, T-bet, GATA-3, phosphorylated STAT3, RORgt, RORa, FOXO1, FOXO3, HIF1 -a and Satb1.

Regulatory T lymphocytes

Bitesized immunology, British Society of Immunology

3. Subpopulations of Treg cells

There are three main subpopulations of Treg based on their anatomical localization and differentiation. Formerly called “natural” Tregs have now been renamed to Treg derived from the thymus, thymic or tTreg, as a special line in the development of CD4+ thymocytes. tTreg  have a T cell receptor (TCR) of high affinity for self-antigens.

Peripheral Treg (pTreg) differentiate at the periphery after antigen recognition, while in vitro generated Treg cells (iTreg cells) can be obtained from naive T cells in the presence of TCR signaling and additional factors such as IL-2 and TGF-β. There are markers that make it possible to distinguish between pTreg and tTreg, such as Helios and Neuropilin-1.

Treg are also defined as both central (cTreg) and effector (eTreg) cells in peripheral lymphoid organs. cTreg are resting cells and represent most of the Treg in secondary lymphoid organs and express high levels of CD62L and CCR7, similar to naive conventional T cells. In contrast, effector eTreg cells express high levels of CD44 or ICOS surface markers.

4. Treg in non-lymphoid organs

Treg cells are found not only in the T cell zones of lymphoid organs, but also in areas of B lymphocytes, where they control the maturation of B cells and the production of antibodies. In addition to lymphoid organs, Treg are found in non-lymphoid tissues such as visceral adipose tissue, skeletal muscle, skin, colon, and lungs where they maintain homeostasis. Treg are specifically adapted to the tissue in which they are located, which implies the acquisition of the effector phenotype with the expression of effector molecules, chemokines and their receptors and cytokines. It is believed that transcription programs of various factors must be established in non-lymphoid tissue that maintain Treg identity and allow their tissue adaptation. Dynamic adaptation of Treg results in the acquisition of an effector phenotype and co-expression of transcription factors such as T-bet, IRF-4, GATA-3, STAT3, or BCL6. Thus, the generation of functionally different Treg subpopulations is initiated, which are localized at the sites of inflammation and acquire tissue-specific suppressive functions. However, during this process, the instability and plasticity of Treg can occur, especially at the sites of inflammation, which affects the  molecular difference between effector and regulatory T cells. Recent data show a significant overlap between phenotype and function of Treg and effector T lymphocytes.

Scheinecker C, Göschl L, Bonelli M. Treg cells in health and autoimmune diseases: New insights from single cell analysis. J Autoimmun. 2020 Jun;110:102376. doi: 10.1016/j.jaut.2019.102376. Epub 2019 Dec 18. PMID: 31862128.

5. Treg in autoimmune diseases

In the previous post, the mechanisms of immune tolerance that prevent the development of autoimmune diseases were discussed. Autoimmune diseases occur when self-antigens (autoantigens) presented on the membrane of antigen-presenting cells (APCs) are recognized by autoreactive T and B lymphocytes when their activation, proliferation and production of cytokines and autoantibodies occur, leading to tissue damage and organ dysfunction.

Treg play a significant role in the development of many autoimmune diseases such as type 1 diabetes, autoimmune hemolytic anemia (AHA), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome, systemic sclerosis and others.

Treg were originally shown in the secondary lymphoid organs and peripheral blood. However, Treg express a series of adhesive molecules and chemokine receptors that control the migration of Treg into lymphoid as well as non-lymphoid organs.

For example, migration and retention of Treg in skin depends on the ability to express carbohydrate ligands for P-selectin and E-selectin on endothelial cells, and the lack of these ligands on Treg cells results in the development of autoimmunity in the skin. CCR7 deficiency blocks the migration of Treg cells into lymph nodes and inhibits Treg function in an experimental model of colitis.

Treg acquire different characteristics, they adapt to the immune response that they suppress. For example, Treg cells increase the expression of the T-bet transcription factor, which is required for the suppression of the Th1 response, IRF4 for the suppression of the Th2 response, STAT3 for the suppression of the Th17 response, and GATA-3, for the control of effector T cells.

Characterization of the cellular and molecular mechanisms underlying the functional specificity of Treg in different tissues may be crucial for finding new Treg-based therapies in autoimmune diseases.

6. Mechanisms by which Treg suppresses the immune response

Treg have several mechanisms at their disposal that mediate their suppressive effects. Suppressive mechanisms can be grouped into four basic “modes of action”: suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic dysfunction, and suppression by modulation of maturation or dendritic cell (DC) function.

  • Suppression of inhibitory cytokines: interleukin-10 (IL-10), transforming growth factor-β (TGF-β) and IL-35 are key cytokines that mediate Treg induced immunosuppression.
  • Suppression by cytolysis: Treg induce cytolysis via granzyme A and / or granzyme B and perforin.
  • Suppression by metabolic dysfunction: cytokine-deficient apoptosis results from rapid consumption of IL-2 by CD25+ Treg, while adenosine production and intracellular cyclic AMP expose the target cells to these potent inhibitory molecules.
  • Suppression by modulation of maturation or function of dendritic cells: two mechanisms have been proposed. First, CTLA4 – CD80/CD86 interactions induce the release of indoleamine 2,3-dioxygenase (IDO), a potent immunosuppressive molecule that triggers tryptophan catabolism and formation of pro-apoptotic metabolites.
    Second, LAG3 (CD223) that binds to MHC class II molecules inhibits maturation and DC function.

Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008
Jul;8(7):523-32. doi: 10.1038/nri2343. PMID: 18566595; PMCID: PMC2665249.

If you have questions, comments and suggestions for topics I will be happy to answer.

Literature

  1. Scheinecker C, Göschl L, Bonelli M. Treg cells in health and autoimmune diseases: New insights from single cell analysis. J Autoimmun. 2020 Jun;110:102376. doi: 10.1016/j.jaut.2019.102376. Epub 2019 Dec 18. PMID: 31862128.
  2. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008 Jul;8(7):523-32. doi: 10.1038/nri2343. PMID: 18566595; PMCID: PMC2665249.
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[…] (Treg) are one of the subpopulations of T lymphocytes that play a key role in maintaining peripheral tolerance (link), preventing autoimmunity and limiting chronic inflammatory diseases. Decreased or impaired […]

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[…] is one of the subpopulations of T lymphocytes that play a key role in maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammatory diseases. Treg cells express FoxP3 and […]

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