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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1225-1232.
Prepublished online as a Blood First Edition Paper on April 20, 2007; DOI 10.1182/blood-2006-12-064527.
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IMMUNOBIOLOGY
Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression
Giovanna Borsellino1,
Markus Kleinewietfeld2,
Diletta Di Mitri1,
Alexander Sternjak2,
Adamo Diamantini1,
Raffaella Giometto1,
Sabine Höpner2,
Diego Centonze3,
Giorgio Bernardi3,
Maria Luisa Dell'Acqua4,
Paolo Maria Rossini4,
Luca Battistini1,
Olaf Rötzschke2, and
Kirsten Falk2
1 Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy;
2 Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany;
3 Neurology Unit, Università di Roma Tor Vergata, Rome, Italy,
4 Neurology Unit, University of Rome Campus Biomedico, Rome, Italy
In the immune system, extracellular ATP functions as a "natural adjuvant" that exhibits multiple proinflammatory effects. It is released by damaged cells as an indicator of trauma and cell death but can be inactivated by CD39 (nucleoside triphosphate diphosphohydrolase-1 [NTPDase 1]), an ectoenzyme that degrades ATP to AMP. Here, we show that CD39 is expressed primarily by immune-suppressive Foxp3+ regulatory T (Treg) cells. In mice, the enzyme is present on virtually all CD4+CD25+ cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation. Activated Treg cells are therefore able to abrogate ATP-related effects such as P2 receptor-mediated cell toxicity and ATP-driven maturation of dendritic cells. Also, human Treg cells express CD39. In contrast to mice, CD39 expression in man is restricted to a subset of Foxp3+ regulatory effector/memory-like T (TREM) cells. Notably, patients with the remitting/relapsing form of multiple sclerosis (MS) have strikingly reduced numbers of CD39+ Treg cells in the blood. Thus, in humans CD39 is a marker of a Treg subset likely involved in the control of the inflammatory autoimmune disease.
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