Mechanisms of Regulatory T Cell-Mediated Suppression

Mechanisms of Regulatory T Cell-Mediated Suppression

Regulatory T cells (Tregs) are a heterogeneous subset of CD4⁺ T cells with immunosuppressive properties that are required to maintain immune homeostasis and self-tolerance, dampen inflammation, and prevent autoimmunity. Tregs function by inhibiting the activities of CD4⁺ and CD8⁺ effector T cells (Teff cells), natural killer (NK) cells, NKT cells, and antigen-presenting cells through multiple mechanisms. These include the secretion of inhibitory cytokines, disruption of effector T cell metabolism, production of cytolytic factors, induction of infectious tolerance, and modulation of dendritic cell maturation or function. Treg cell deficiency or dysregulated Treg cell functions are associated with inflammatory and autoimmune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, and systemic lupus erythematosus. Conversely, increases in either the number of Tregs or Treg activity can also be pathogenic under conditions where they suppress beneficial anti-viral or anti-tumor immune responses.

One mechanism by which Tregs suppress T cell-mediated immune responses is through the secretion of immunosuppressive cytokines such as TGF-β, IL-10, and IL-35. Each of these cytokines is involved in inhibiting the differentiation, proliferation, and activation of Teff cells, suppressing cytokine production by Teff cells, and promoting the conversion of activated T conventional (Tconv) cells to cells with an immunosuppressive phenotype. LAP-TGF-β1 complexed with LRRC32/GARP on the surface of Tregs can also suppress the proliferation of activated T cells either through the release and activation of TGF-β1 or through a cell contact-dependent mechanism. In addition, Tregs secrete or express cell-bound Galectin-1, which promotes growth arrest and apoptosis of Teff cells. Besides their direct suppressive activities, TGF-β1, IL-10, and IL-35 play a role in the induction of infectious tolerance, which leads to the conversion of activated Tconv to T cells with a regulatory phenotype. TGF-β stimulates the conversion of CD4⁺CD25^-FoxP3^- Tconv cells to CD4⁺CD25⁺FoxP3⁺ T suppressor cells (in mouse), while IL-10 and IL-35 promote the conversion of Tconv cells to IL-10, TGF-β1-secreting Tr1 cells or IL-35-expressing iTregs, respectively. Treg expansion by these mechanisms may play a critical role in maintaining immune homeostasis and protecting tissues from inflammation-induced damage.

Another mechanism by which Tregs suppress effector T cell functions is through metabolic disruption. High level expression of IL-2 Rα/CD25 on the surface of Tregs has been suggested to deplete local IL-2, leading to deprivation-mediated Teff cell apoptosis. Tregs also inhibit Teff cell proliferation and IL-2 synthesis by directly transferring inhibitory cAMP through the gap junctions of Teff cells. Additionally, Tregs express high levels of the ectoenzymes, CD39 and CD73 on their surfaces, resulting in the CD39-mediated degradation of ATP or ADP to AMP and the production of adenosine from extracellular AMP by CD73. Degradation of ATP or ADP to AMP inhibits dendritic cell maturation, while adenosine binds to A_2A receptors on Teff cells and inhibits their proliferation and activity. Adenosine also promotes a tolerogenic phenotype in dendritic cells, inhibits the activity of NK cells, and increases both the number of Tregs and their immunosuppressive activity.

Similar to NK cells and CD8⁺ cytotoxic T lymphocytes, Tregs have also been found to secrete granzymes, which account at least in part for their immunosuppressive properties. Tregs from granzyme B-deficient mice were shown to have lower levels of suppressive activity in vitro and have been suggested to induce Teff cell apoptosis in a granzyme B-dependent, perforin-independent manner. In addition, Tregs have been shown to induce cytolysis of B cells, NK cells, and CD8⁺ T cells in a granzyme B-, perforin-dependent manner.

Finally, Tregs are thought to indirectly regulate the activity of Teff cells by blocking the maturation or antigen-presenting capabilities of dendritic cells. Constitutive expression of CTLA-4 on the surface of Tregs down regulates dendritic cell expression of B7-1/CD80 and B7-2/CD86, two T cell co-stimulatory proteins that bind to T cell-expressed CD28 to promote T cell activation. Binding of CD80 and/or CD86 by CTLA-4 also triggers dendritic cells to produce indoleamine 2,3-dioxygenase (IDO). This immunosuppressive molecule induces the production of pro-apoptotic metabolites from tryptophan catabolism, leading to the suppression of Teff cell activity. In addition, Tregs express LAG-3, which binds to MHC class II molecules on immature dendritic cells, blocking their maturation and limiting T cell-mediated immune responses.

To learn more, explore the following Regulatory T cell-related resources:

Regulatory T Cells (Tregs) Research Area page

Regulatory T Cell Markers

Current and Emerging Immune Checkpoint Targets for Immuno-Oncology Research eBook

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