Review
Feature Review
CD39 and CD73 in immunity and inflammation

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Highlights

  • CD39 and CD73 are important for calibrating the duration, magnitude, and composition of the ‘purinergic halo’ surrounding immune cells.

  • CD39 and CD73 degrade ATP, ADP, and AMP to adenosine; they can be viewed as ‘immunological switches’ that shift ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine.

  • CD39 and CD73 are highly expressed on the surface of Foxp3+ Tregs and have been increasingly used as markers of Tregs.

  • CD39 and CD73 are important for the immunosuppressive activity of Tregs.

  • CD39 and CD73 generate an immunosuppressed environment, characterized by increased adenosine levels, which promotes the development and progression of cancer.

The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia–reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders.

Section snippets

How the purinergic system shapes immune/inflammatory responses

The immune system is a tightly regulated and integrated cell network that functions to preserve and restore homeostasis. This task is accomplished by patrolling organs for signs of microbial invasion or tissue injury and triggering defensive inflammatory and restitutive responses following infection and injury [1]. However, inappropriate activation of the immune system can lead to unacceptable levels of collateral tissue damage and the development of various pathophysiological conditions, such

Molecular biology and regulation of CD39 and CD73

CD39 is an integral membrane protein that phosphohydrolyzes ATP, and less efficiently ADP, in a Ca2+- and Mg2+-dependent manner, to yield AMP [18]. Human CD39 is a putative 510-amino acid protein with seven potential N-linked glycosylation sites, 11 Cys residues, and two transmembrane regions [19]. Structurally, it is characterized by two transmembrane domains, a small cytoplasmic domain comprising the NH2- and COOH-terminal segments, and a large extracellular hydrophobic domain, which includes

The function of CD39 and CD73 in cells of the immune system

Given that the combination of CD39 and CD73 degrade ATP, ADP, and AMP to adenosine, they can be viewed as ‘immunological switches’ that shift ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine (Figure 1) [36]. In addition to host cells, several pathogens (i.e., Escherichia coli, Staphylococcus aureus, Toxoplasma gondii, and Trichomonas vaginalis) are endowed with a streamlined CD39/CD73-like machinery, which fosters the establishment and

Regulation of immunity by ectonucleotidases in infections

There is increasing evidence that the ability of several microorganisms to evade the control of the immune system arises from their high nucleotide metabolic versatility, which favors their invasion of and dissemination in the host [80]. Pathogens can also exploit ectonucleotidases located on the outer surface of a cell or tissue to generate an adenosine-rich milieu, which allows them to escape immune surveillance 81, 82, 83, 84, 85. By contrast, in certain scenarios, CD39 and CD73 can also

Regulation of immunity by CD39 and CD73 in autoimmune diseases

Alteration of the CD39/CD73 machinery can disrupt the complex mechanisms underlying immune tolerance to self-antigens, driven mainly by Tregs, thus contributing to the development of several autoimmune diseases [25].

Regulation of immunity by CD39 and CD73 in allergic diseases

The growing awareness about the involvement of purinergic signaling in shaping immune and inflammatory responses during allergic reactions [112] has fostered scientific interest in the roles of CD39 and CD73 in this context. Recently, a key role for CD73 has been unraveled in the development of airway inflammation after allergen exposure, as mice lacking CD73 display reduced airway hyperresponsiveness to methacholine as well as decreased eosinophil and mast cell infiltration, as compared with

Regulation of immunity by CD39 and CD73 in ischemia–reperfusion injury

Multiple lines of evidence have demonstrated that adenosine, produced as a result of the coordinated function of CD39 and CD73, is pivotal in protecting tissue against hypoxic and ischemic insults. Early studies, based on both genetic knockout models and pharmacological inhibition of CD39 and CD73 in mice, showed that these enzymes are crucial for protecting against increased vascular permeability and neutrophil extravasation during local hypoxia 32, 34, 59. The increased vascular permeability

Regulation of immunity by CD39 and CD73 in atherosclerosis and arterial calcification

Current knowledge about the complex mechanisms underlying the pathogenesis of atherosclerosis highlights the importance of several immune/inflammatory mediators in the initiation and progression of this disorder [129], and vascular CD39 and CD73 regulate several steps in the atherogenic process by governing purinergic signaling 130, 131.

Apolipoprotein E (ApoE) knockout mice, an experimental model of atherosclerosis, show decreased CD39 expression and activity in thoracic aorta, which correlates

Regulation of immunity by CD39 and CD73 in diabetes

The term diabetes denotes a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both [139]. Diabetes can result from the autoimmune destruction of β cells in the pancreas with consequent insulin deficiency (type 1 diabetes) or abnormalities of adipose tissue, liver, and muscle that result in resistance to insulin action (type 2 diabetes) [139].

A recent study has demonstrated that the susceptibility of mice to

Regulation of immunity by CD39 and CD73 in cancer

Increasing evidence suggests that interactions between tumor cells and their microenvironment are essential for tumorigenesis [145]. Within the neoplastic milieu, cancer and immune cells closely interact to generate an immunosuppressive environment by releasing immunomodulatory factors, which supports neoplastic growth [146].

Several studies have pointed to the critical task carried out by CD39 and CD73 in generating this immunosuppressed environment, characterized by increased adenosine levels,

Concluding remarks

Over the past 30 years, increasing evidence has underscored the role of the purinergic system in coordinating tissue immune responses under both physiological conditions and in the presence of inflammation. In this context, the CD39/CD73 pathway is a critical checkpoint; through its coordinated activity, it regulates the types and level of purinergic receptor activation, by finely shaping the chemistry, magnitude, and duration of purinergic signaling, in accordance with the various

Acknowledgments

This work was supported by National Institutes of Health grant R01GM66189 and USAMRMC grant 09065004.

Glossary

Arteriogenesis
describes the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses in response to ischemia.
Atheroma
is an asymmetric focal thickening of the intima. The atheroma is composed of a lipid core, a residue of necrotic ‘foam cell-forming macrophages’, that migrate into the intima and ingest lipids, as well as by a connective tissue matrix derived from smooth muscle cells that migrate from the media into the intima, where they proliferate and change

References (174)

  • F. Chalmin

    Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression

    Immunity

    (2012)
  • K. Knapp

    Crystal structure of the human ecto-5′-nucleotidase (CD73): insights into the regulation of purinergic signaling

    Structure

    (2012)
  • P.A. Beavis

    CD73: a potent suppressor of antitumor immune responses

    Trends Immunol.

    (2012)
  • M. Mandapathil

    Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression

    J. Immunol. Methods

    (2009)
  • P.J. Schuler

    Separation of human CD4+CD39+ T cells by magnetic beads reveals two phenotypically and functionally different subsets

    J. Immunol. Methods

    (2011)
  • G. Borsellino

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

    Blood

    (2007)
  • K.M. Dwyer

    Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype

    Am. J. Transplant.

    (2010)
  • M. Mandapathil

    Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells

    J. Biol. Chem.

    (2010)
  • H.K. Eltzschig

    Neutrophils as sources of extracellular nucleotides: functional consequences at the vascular interface

    Trends Cardiovasc. Med.

    (2008)
  • G. Haskó et al.

    Adenosine: an endogenous regulator of innate immunity

    Trends Immunol.

    (2004)
  • E.D. Pulte

    CD39/NTPDase-1 activity and expression in normal leukocytes

    Thromb. Res.

    (2007)
  • H.K. Eltzschig

    Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism

    Blood

    (2004)
  • R. Corriden

    Ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1/CD39) regulates neutrophil chemotaxis by hydrolyzing released ATP to adenosine

    J. Biol. Chem.

    (2008)
  • L. Airas et al.

    CD73 mediates adhesion of B cells to follicular dendritic cells

    Blood

    (1996)
  • B. Atkinson

    Ecto-nucleotidases of the CD39/NTPDase family modulate platelet activation and thrombus formation: potential as therapeutic targets

    Blood Cells Mol. Dis.

    (2006)
  • C.Y. Fung

    P2X(1) receptor inhibition and soluble CD39 administration as novel approaches to widen the cardiovascular therapeutic window

    Trends Cardiovasc. Med.

    (2009)
  • A. Ålgars

    Different role of CD73 in leukocyte trafficking via blood and lymph vessels

    Blood

    (2011)
  • V. Kak

    Immunotherapies in infectious diseases

    Med. Clin. North Am.

    (2012)
  • M.C. de Souza

    The influence of ecto-nucleotidases on Leishmania amazonensis infection and immune response in C57B/6 mice

    Acta Trop.

    (2010)
  • T. Russo-Abrahão

    Giardia duodenalis: biochemical characterization of an ecto-5′-nucleotidase activity

    Exp. Parasitol.

    (2011)
  • A.M. Kas-Deelen

    Cytomegalovirus infection increases the expression and activity of ecto-ATPase (CD39) and ecto-5′nucleotidase (CD73) on endothelial cells

    FEBS Lett.

    (2001)
  • D.B. Leal

    HIV infection is associated with increased NTPDase activity that correlates with CD39-positive lymphocytes

    Biochim. Biophys. Acta

    (2005)
  • B. Crimeen-Irwin

    Failure of immune homeostasis – the consequences of under and over reactivity

    Curr. Drug. Targets Immune Endocr. Metabol. Disord.

    (2005)
  • G. Haskó

    Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

    Nat. Rev. Drug Discov.

    (2008)
  • A. Trautmann

    Extracellular ATP in the immune system: more than just a ‘danger signal’

    Sci. Signal.

    (2009)
  • W.G. Junger

    Immune cell regulation by autocrine purinergic signalling

    Nat. Rev. Immunol.

    (2011)
  • B. Sperlágh et al.

    The role of extracellular adenosine in chemical neurotransmission in the hippocampus and basal ganglia: pharmacological and clinical aspects

    Curr. Top. Med. Chem.

    (2011)
  • B.B. Fredholm

    International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors – an update

    Pharmacol. Rev.

    (2011)
  • M.R. Schetinger

    NTPDase and 5′-nucleotidase activities in physiological and disease conditions: new perspectives for human health

    Biofactors

    (2007)
  • M. Nikolova

    CD39/adenosine pathway is involved in AIDS progression

    PLoS Pathog.

    (2011)
  • F. Bönner

    Resident cardiac immune cells and expression of the ectonucleotidase enzymes CD39 and CD73 after ischemic injury

    PLoS ONE

    (2012)
  • J. Bastid

    ENTPD1/CD39 is a promising therapeutic target in oncology

    Oncogene

    (2012)
  • B. Zhang

    CD73 promotes tumor growth and metastasis

    Oncoimmunology

    (2012)
  • P. Heine

    The C-terminal cysteine-rich region dictates specific catalytic properties in chimeras of the ectonucleotidases NTPDase1 and NTPDase2

    Eur. J. Biochem.

    (2001)
  • C.R. Maliszewski

    The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization

    J. Immunol.

    (1994)
  • K. Enjyoji

    Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation

    Nat. Med.

    (1999)
  • N. Mizumoto

    CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness

    Nat. Med.

    (2002)
  • K.M. Dwyer

    CD39 and control of cellular immune responses

    Purinergic Signal.

    (2007)
  • G.G. Yegutkin

    Metabolism of circulating ADP in the bloodstream is mediated via integrated actions of soluble adenylate kinase-1 and NTPDase1/CD39 activities

    FASEB J.

    (2012)
  • N. Sträter

    Ecto-5′-nucleotidase: structure function relationships

    Purinergic Signal.

    (2006)
  • Cited by (854)

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