1. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.
- Author
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Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell'Acqua ML, Rossini PM, Battistini L, Rötzschke O, and Falk K
- Subjects
- Adult, Animals, Dendritic Cells cytology, Dendritic Cells metabolism, Female, Humans, Hydrolysis, Male, Mice, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting physiopathology, Adenosine Triphosphate metabolism, Antigens, CD metabolism, Apyrase metabolism, Forkhead Transcription Factors immunology, Forkhead Transcription Factors metabolism, Immunosuppression Therapy, Multiple Sclerosis, Relapsing-Remitting immunology, T-Lymphocytes, Regulatory immunology
- Abstract
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 (T(REM)) 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.
- Published
- 2007
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