Foxp3+CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism

doi:10.1016/j.it.2007.12.005

Trends in Immunology

Volume 29, Issue 3, March 2008, Pages 99-102

https://doi.org/10.1016/j.it.2007.12.005 Get rights and content

Foxp3⁺CD4⁺ T cells represent a population of naturally arising suppressor T cells that are crucial for the control of autoimmune responses. The suppressive activity of this T cell subset relies on multiple mechanisms that include secretion of anti-inflammatory factors such as TGF-β or IL-10. Novel studies now establish that, through the generation of the immunosuppressive factor adenosine, the ectoenzymes CD39 and CD73 are important contributors to the regulatory activity of Foxp3⁺CD4⁺ T cells.

Section snippets

Adenosine and Foxp3⁺CD4⁺ suppressor T cell activity

Among various physiological effects, the nucleoside adenosine possesses efficient anti-inflammatory and antiproliferative properties mediated by G protein-coupled purinergic receptors of the P1 class on the surface of immune cells. These include the A2A receptor (A2AR), which is expressed on T lymphocytes 1, 2. For instance, A2AR engagement is involved in the T cell-mediated suppression of inflammatory bowel diseases, as shown by the fact that CD45RB^high pathogenic T cells lacking A2AR escape

The ectonucleotidase CD39 is expressed on Foxp3⁺CD4⁺ suppressor T cells

E-NTPDases are enzymes that degrade nucleoside tri- and -diphosphates (NTDPs) into nucleoside monophosphate (NMP). CD39 is the dominant member of this family in the immune system. CD39 is expressed on Langerhans cells, most monocytes, B cells, and ∼10% of CD4⁺ T cells in mouse lymphoid organs [4]. Unlike CD39⁻CD4⁺ T cells, CD39⁺CD4⁺ T cells coexpress CD25, glucocorticoid-induced tumor necrosis factor receptor (GITR), and CTLA-4 molecules that are commonly found on Foxp3⁺CD4⁺ T cells. More

CD39 controls adenosine generation that contributes to Foxp3⁺CD4⁺ T cell-mediated immunosuppression

The importance of CD39 expression by Foxp3⁺CD4⁺ T cells lies in the fact that its NTPDase activity, and therefore the production of 5′-AMP, appears to be coupled to the activation status of the cells [12]. In other words, CD39 activity impacts on CD73 activity and therefore on the extracellular production of the nucleoside adenosine. Unlike wild-type CD4⁺ T cells that rapidly hydrolyze exogenous ADP and generate adenosine, CD4⁺ T cells from CD39-deficient mice show a markedly diminished ADP

CD39 nucleotidase activity regulates Foxp3⁺CD4⁺ suppressor T cells themselves

CD39-deficient mice possess peripheral CD4⁺CD25⁺ T cells that express Foxp3 and are numerically indistinguishable from their wild-type counterparts, indicating that CD39 activity plays no role in Foxp3⁺CD4⁺ T cell development. However, cd39^−/−CD25⁺CD4⁺ T cells show unusual signs of activation (elevated CD25 and CTLA-4 expression levels) and proliferate excessively (i.e. are not anergic) in vitro in response to various stimuli, even in the absence of exogenous IL-2, probably reflecting the loss

Is extracellular nucleotide catabolism a common theme in suppressor T cell activity?

As always, novel observations raise novel questions. For example, one might wonder whether extracellular nucleotide catabolism contributes in a similar or differential fashion to immunoregulation mediated by CD4⁺ suppressor T cells in lymphoid organs versus inflamed tissues (Box 1), such as within the central nervous system during the recovery phase of experimental autoimmune encephalomyelitis [17]. Future studies are also needed to establish whether the CD39 and CD73 axis that appears to be

Acknowledgements

M.S.B. is supported partly by National Institutes of Health grant AI57854. C.V. is supported by the Centre National de la Recherche Scientifique.

References (20)

M.V. Sitkovsky et al.
The ‘danger’ sensors that stop the immune response: the A2 adenosine receptors?
Trends Immunol.
(2005)
M. Odashima
Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease
Gastroenterology
(2005)
S. Huang
Role of A2A extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion
Blood
(1997)
G. Borsellino
Expression of ectonucleotidase CD39 by Foxp3⁺ Treg cells: hydrolysis of extracellular ATP and immune suppression
Blood
(2007)
M.V. Sitkovsky
Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors
Annu. Rev. Immunol.
(2004)
M. Naganuma
Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis
J. Immunol.
(2006)
S. Deaglio
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression
J. Exp. Med.
(2007)
A. Ohta et al.
Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage
Nature
(2001)
J.J. Kobie
T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine
J. Immunol.
(2006)
R. Resta
Ecto-enzyme and signaling functions of lymphocyte CD73
Immunol. Rev.
(1998)

There are more references available in the full text version of this article.

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It is well known that sepsis inhibits immune homeostasis by inducing an initial intense systemic inflammatory response, rapidly followed by immunoparalysis [31]. In order to explain the immunoparalysis, multiple mechanisms have been proposed, including the excessive activation of Tregs [32]. CD4+ CD25+ Tregs play a critical role in the negative regulatory response by generating anti-inflammatory cytokines, such as IL-10, which may lead to immune paralysis in late sepsis [27].
The aim of our study was to investigate the effect of lentinan on regulatory T cells (Tregs) in sepsis, especially on the generation of interleukin (IL)-10 via regulation of Erk–FoxO1 signaling.
BalB/c mice were randomized into five groups: sham group, the group with burns plus Pseudomonas aeruginosa infection, and the groups with burns plus P. aeruginosa infection administered 40, 100, and 250 mg/kg of lentinan. The mice were sacrificed on postburn days 0, 1, 2, 3, and 4, respectively, with eight animals per group at each time point. The peripheral blood CD4⁺ CD25⁺ Tregs and CD4⁺ T cells were isolated using magnetic microbeads. The phenotypes were analyzed by flow cytometry. The cytokine levels were determined with enzyme-linked immunosorbent assay (ELISA). Signal transduction was studied by Western blot, quantitative polymerase chain reaction (qPCR), and luciferase assay.
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We therefore hypothesized that this could provide at least one possible mechanism by which GMaM exert their anti-inflammatory function directly in the intestine by sequestering ATP, or by interaction with cells of the adaptive immune system by providing adenosine. Until now, it was thought that Treg form an autocrine loop using self-generated adenosine that binds to Treg-expressed adenosine receptors (eg, A2AR) resulting in Treg expansion and higher Foxp3 expression.29,49 However, it remains unproven as to whether these activities degrading ATP to adenosine could be provided by a second cell type that is surrounding the cell, in our case the monocyte, with an adenosine-rich “purinergic halo,” thereby modifying cells in close proximity.
Granulocyte macrophage colony-stimulating factor (GM-CSF) treatment induces clinical response in patients with active Crohn’s disease. To explore whether monocytes mediate GM-CSF effects in vivo, we used a mouse model of chronic colitis induced by dextran sulfate sodium (DSS).
Murine bone marrow-derived monocytes were activated with GM-CSF in vitro, and gene expression, phenotype, and function of GM-CSF-activated monocytes (GMaM) were analyzed. Therapeutic effects of GMaM were assessed in a model of chronic colitis induced by repeated cycles of DSS. Monocytes were administered intravenously and their immunomodulatory functions were evaluated in vivo by clinical monitoring, histology, endoscopy, immunohistochemistry, and expression of inflammatory markers in the colon. The distribution of injected monocytes in the intestine was measured by in vivo imaging.
GMaM expressed significantly higher levels of anti-inflammatory molecules. Production of reactive oxygen species was also increased while phagocytosis and adherence were decreased. GMaM up-regulated CD39 and CD73, which allows the conversion of adenosine triphosphate into adenosine and coincided with the induction of Foxp3⁺ (forkhead-box-protein P3 positive) regulatory T cells (Treg) in cocultures of GMaM and naive T cells. In chronic DSS-induced colitis, adoptive transfer of GMaM led to significant clinical improvement, as demonstrated by reduced weight loss, inflammatory infiltration, ulceration, and colon shrinkage. As GMaM migrated faster and persisted longer in the inflamed intestine compared with control monocytes, their presence induced Treg generation in vivo.
GM-CSF leads to specific monocyte activation that modulates experimental colitis via mechanisms that include the induction of Treg. We demonstrate a possible mechanism of Treg induction through CD39 and CD73 expression on monocytes.
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We and others have recently described the presence of an ectonucleotidase, CD39, as a new functional surface marker for Treg [60–62]. CD39 hydrolyzes exogenous ATP to ADP and 5′AMP, which is further hydrolyzed to adenosine by another ectonucleotidase, CD73 [63]. Murine Treg express CD73 on the cell surface, while in human Treg it is found in the cytoplasm but only after vigorous cell permeabilization (T. Whiteside, unpublished data).
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Trends in Immunology

Section snippets

Adenosine and Foxp3⁺CD4⁺ suppressor T cell activity

The ectonucleotidase CD39 is expressed on Foxp3⁺CD4⁺ suppressor T cells

CD39 controls adenosine generation that contributes to Foxp3⁺CD4⁺ T cell-mediated immunosuppression

CD39 nucleotidase activity regulates Foxp3⁺CD4⁺ suppressor T cells themselves

Is extracellular nucleotide catabolism a common theme in suppressor T cell activity?

Acknowledgements

References (20)

The ‘danger’ sensors that stop the immune response: the A2 adenosine receptors?

Trends Immunol.

Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease

Gastroenterology

Role of A2A extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion

Blood

Expression of ectonucleotidase CD39 by Foxp3⁺ Treg cells: hydrolysis of extracellular ATP and immune suppression

Blood

Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors

Annu. Rev. Immunol.

Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis

J. Immunol.

Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression

J. Exp. Med.

Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage

Nature

T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine

J. Immunol.

Ecto-enzyme and signaling functions of lymphocyte CD73

Immunol. Rev.

Cited by (38)

Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease

Lentinan ameliorates burn sepsis by attenuating CD4<sup>+</sup> CD25<sup>+</sup> Tregs

Granulocyte Macrophage Colony-Stimulating Factor-Activated CD39<sup>+</sup>/CD73<sup>+</sup> Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells

Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment

What are regulatory T cells (Treg) regulating in cancer and why?

Biologic Agents in Crohn's Patients Reduce CD4<sup>+</sup>T Cells Activation and Are Inversely Related to Treg Cells

Trends in Immunology

UpdateResearch FocusFoxp3+CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism

Section snippets

Adenosine and Foxp3+CD4+ suppressor T cell activity

The ectonucleotidase CD39 is expressed on Foxp3+CD4+ suppressor T cells

CD39 controls adenosine generation that contributes to Foxp3+CD4+ T cell-mediated immunosuppression

CD39 nucleotidase activity regulates Foxp3+CD4+ suppressor T cells themselves

Is extracellular nucleotide catabolism a common theme in suppressor T cell activity?

Acknowledgements

Trends Immunol.

Gastroenterology

Blood

Blood

Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors

Annu. Rev. Immunol.

Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis

J. Immunol.

Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression

J. Exp. Med.

Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage

Nature

T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine

J. Immunol.

Ecto-enzyme and signaling functions of lymphocyte CD73

Immunol. Rev.

Update
Research Focus
Foxp3⁺CD4⁺ T cell-mediated immunosuppression involves extracellular nucleotide catabolism

Adenosine and Foxp3⁺CD4⁺ suppressor T cell activity

The ectonucleotidase CD39 is expressed on Foxp3⁺CD4⁺ suppressor T cells

CD39 controls adenosine generation that contributes to Foxp3⁺CD4⁺ T cell-mediated immunosuppression

CD39 nucleotidase activity regulates Foxp3⁺CD4⁺ suppressor T cells themselves