Mechanisms of Regulatory T Cell-Mediated Suppression

Click on the mechanisms of regulatory T cell-mediated suppression listed on the left below to see the specific Treg-associated molecules that are involved in each mechanism and an explanation of how they negatively regulate the immune response.

Latent TGF-beta 1
Latent TGF-beta 1
alpha V-beta Integrins
alpha V-beta Integrins
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Active TGF-beta 1
Active TGF-beta 1
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IL-10
IL-10
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IL-35
IL-35
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Galectin-1
Galectin-1
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IL-10
IL-10
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IL-10 R
IL-10 R
IL-35
IL-35
IL-35 R
IL-35 R
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Galectin-1
Galectin-1
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Integrin alpha 4 beta 1 or Integrin alpha 5 beta 1
Integrin alpha 4 beta 1 or Integrin alpha 5 beta 1
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GM1
GM1
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TGF-beta R
TGF-beta R
Latent TGF-beta 1
Latent TGF-beta 1
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LRRC32
LRRC32
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TGF-beta R
TGF-beta R
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Galectin-1
Galectin-1
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GM1
GM1
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Integrin alpha 4 beta 1 or
Integrin alpha 5 beta 1
Integrin alpha 4 beta 1 or
Integrin alpha 5 beta 1
TRPC5
TRPC5
Ca2+
Ca2+
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Effector T Cell
Effector T Cell
CD4+CD25+
Regulatory T Cell
CD4+CD25+
Regulatory T Cell
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FoxP3
FoxP3
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IL-2 R
IL-2 R
Effector T Cells
Effector T Cells
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CD39
CD39
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ATP/ADP
ATP/ADP
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AMP
AMP
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CD73
CD73
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Adenosine
Adenosine
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A2A R
A2A R
A2A/2B R
A2A/2B R
APC
APC
A2A R
A2A R
Effector T Cell
Effector T Cell
A2A R
A2A R
NK Cell
NK Cell
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cAMP
cAMP
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Effector
T Cell
Effector
T Cell
Granzyme A/B
Granzyme A/B
Effector T Cell
Effector T Cell
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Perforin
Perforin
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Dendritic Cell
Dendritic Cell
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Perforin
Perforin
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NK Cell
NK Cell
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Perforin
Perforin
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IL-10
IL-10
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IL-35
IL-35
Latent TGF-beta 1
Latent TGF-beta 1
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LRRC32
LRRC32
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alpha V-beta
Integrins
alpha V-beta
Integrins
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Active TGF-beta 1
Active TGF-beta 1
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Metabolic Disruption
Metabolic Disruption

Modulation of APCs

Modulation of APCs

IL-2
IL-2
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FoxP3
FoxP3
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IL-10 R
IL-10 R
IL-35 R
IL-35 R
Activated
Tconv Cell
Activated
Tconv Cell
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IL-10
IL-10
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IL-35
IL-35
Tr1 Cell
Tr1 Cell
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IL-10
IL-10
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TGF-beta 1
TGF-beta 1
iTreg
iTreg
IL-35
IL-35
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CTLA-4
CTLA-4
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CD4
CD4
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TCR-CD3
TCR-CD3
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LAG-3
LAG-3
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NRP-1
NRP-1
CD80/CD86
CD80/CD86
MHC II
MHC II
IDO
IDO
N-formylkynurenine
N-formylkynurenine
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Tryptophan
Tryptophan
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Dendritic Cell
Dendritic Cell

Production of Inhibitory Cytokines

Production of Inhibitory Cytokines

IL-2 R
IL-2 R
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Induction of
Cytolysis

Induction of
Cytolysis

Induction of
Infectious
Tolerance

Induction of
Infectious
Tolerance

Induction of Infectious Tolerance

7. Promote the Conversion of Activated T Conventional Cells to Cells with Immunosuppressive Phenotypes
• TGF-beta 1:Induces FoxP3 expression and converts CD4+CD25 Tconv cells toward a suppressor T cell phenotype
• IL-10:Promotes the conversion of Tconv cells to IL-10-,
TGF-beta 1-secreting Tr1 cells
• IL-35:Promotes the conversion of Tconv cells into IL-35-expressing iTregs

Induction of Cytolysis

6. Secretion of Granzymes A/B
• Granzymes A/B induce apoptosis in Teff cells, dendritic cells, and natural killer (NK) cells in both a perforin-dependent and -independent manner

Metabolic Disruption of Teff Cells

3. High Levels of IL-2 Ralpha/CD25 Expression
• Depletes local IL-2, inhibiting the activation and proliferation of Teff cells and leading to deprivation-mediated Teff cell apoptosis
• IL-2 also maintains CD4+CD25+ Treg cell populations
4. Cell Surface Expression of CD39 and CD73 Leads to the Generation of Extracellular Adenosine
• Activation of A2A receptors on Teff cells inhibits their proliferation and function
• Activation of A2A/A2B receptors on antigen-presenting cells (APCs) promotes their production of immunosuppressive molecules, inhibiting T cell activation
• Activation of A2A receptors on natural killer (NK) cells inhibits their activity
• Activation of A2A receptors on Tregs increases their immunoregulatory activity
• Degradation of ATP or ADP to AMP inhibits ATP-driven dendritic cell maturation
5. Transfer of Inhibitory cAMP through Gap Junctions
• Inhibits Teff cell proliferation and IL-2 gene expression

Production of Inhibitory Cytokines

1. Secretion of TGF-beta 1, IL-10, IL-35, and Galectin-1
• Inhibits the differentiation, proliferation, and activation of Teff cells
• Suppresses cytokine production by Teff cells
• IL-10, IL-35, and TGF-beta 1 promote the conversion of activated T conventional cells toward suppressor T cell phenotypes
2. Cell-bound LAP-TGF-beta 1 and Galectin-1
• LAP-TGF-beta 1: Cell-bound LAP-TGF-beta 1 complexed with LRRC32/GARP suppresses the proliferation of activated T cells either through a cell contact-dependent mechanism or through the release and activation of TGF-beta 1
• Galectin-1: Cell-bound Galectin-1 binds to GM1 on Teff cells and induces cross-linking of associated integrins, which triggers Ca2+ influx via TRPC5 channels, leading to growth arrest and apoptosis of activated Teff cells

Modulation of APCs

8. CTLA-4-dependent Suppression
• CTLA-4 interacts with CD80 and CD86 on dendritic cells (DCs), blocking the ability of DCs to activate naïve T cells and triggering indoleamine 2,3-dioxygenase (IDO) expression, which induces the production of pro-apoptotic metabolites from tryptophan catabolism
9. Binding of LAG-3 to MHC II
• Induces an ITAM-mediated inhibitory signaling pathway, blocking the maturation and antigen-presenting capabilities of DCs

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 A2A 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, please visit our Regulatory T Cells (Tregs) Research Area page.

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