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

Mizumoto, Norikatsu; Kumamoto, Tadashi; Robson, Simon C.; Sévigny, Jean; Matsue, Hiroyuki; Enjyoji, Keiichi; Takashima, Akira

doi:10.1038/nm0402-358

Cited by 301 publications

(315 citation statements)

References 40 publications

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“…4). The relative duration of signaling by these extracellular nucleotides is determined largely by nucleotide degrading ecto-enzymes such as the transmembrane ecto-enzymes CD38 and CD39 (21,39,59).…”

Section: Discussionmentioning

confidence: 99%

“…The duration of extracellular signaling via NAD ϩ is controlled by the CD38 family ecto-NADglycohydrolases/ADP-ribosylcyclases that hydrolyze NAD ϩ to ADP-ribose and the CD203 family of phosphodiesterases that hydrolyze NAD ϩ to nicotinamide mononucleotide and AMP (20,35,36). Similarly, the concentration of ATP and the duration of signaling via ATP in the extracelluar compartment are controlled by the CD39 family of ecto-nucleotidases and the CD203 family of phosphodiesterases which hydrolyze ATP to ADP and/or AMP (37)(38)(39).…”

mentioning

confidence: 99%

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NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Scheuplein

Schwarz²,

Adriouch

et al. 2009

The Journal of Immunology

115

136

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Extracellular NAD+ and ATP trigger the shedding of CD62L and the externalization of phosphatidylserine on murine T cells. These events depend on the P2X7 ion channel. Although ATP acts as a soluble ligand to activate P2X7, gating of P2X7 by NAD+ requires ecto-ADP-ribosyltransferase ART2.2-catalyzed transfer of the ADP-ribose moiety from NAD+ onto Arg125 of P2X7. Steady-state concentrations of NAD+ and ATP in extracellular compartments are highly regulated and usually are well below the threshold required for activating P2X7. The goal of this study was to identify possible endogenous sources of these nucleotides. We show that lysis of erythrocytes releases sufficient levels of NAD+ and ATP to induce activation of P2X7. Dilution of erythrocyte lysates or incubation of lysates at 37°C revealed that signaling by ATP fades more rapidly than that by NAD+. We further show that the routine preparation of primary lymph node and spleen cells induces the release of NAD+ in sufficient concentrations for ART2.2 to ADP-ribosylate P2X7, even at 4°C. Gating of P2X7 occurs when T cells are returned to 37°C, rapidly inducing CD62L-shedding and PS-externalization by a substantial fraction of the cells. The “spontaneous” activation of P2X7 during preparation of primary T cells could be prevented by i.v. injection of either the surrogate ART substrate etheno-NAD or ART2.2-inhibitory single domain Abs 10 min before sacrificing mice.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Scheuplein

Schwarz²,

Adriouch

et al. 2009

The Journal of Immunology

115

136

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“…NTPDase1 is a lymphocyte activation marker and found to be expressed on natural killer cells, monocytes, dendritic cells, and subsets of activated T cells. By modulating purinergic signaling, the enzyme plays a major role in the control of the cellular immune response [43][44][45]. In addition to other tissues, prominent expression of NTPDase1 is observed on vascular endothelium.…”

Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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“…In addition, in another study Mizumoto et al [91] observed that exposure to ATP concentrations of up to 10 mM in CD39−/− mice caused no significant death of CD39−/− dendritic cells (DCs), whereas 2.5 mM ATP was sufficient to kill wild-type DCs. The pretreatment of CD39−/− DCs with soluble apyrase restored ATP responsiveness, demonstrating P2-receptor desensitization in CD39−/− DCs.…”

Section: Immunomodulation and Cell-cell Interactionsmentioning

confidence: 99%

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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

Cited by 301 publications

References 40 publications

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Cellular function and molecular structure of ecto-nucleotidases

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

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