Borsellino Giovanna, Kleinewietfeld Markus, Di Mitri Diletta, Sternjak Alexander, Diamantini Adamo, Giometto Raffaella, Höpner Sabine, Centonze Diego, Bernardi Giorgio, Dell'Acqua Maria Luisa, Rossini Paolo Maria, Battistini Luca, Rötzschke Olaf, Falk Kirsten
Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy.
Blood. 2007 Aug 15;110(4):1225-32. doi: 10.1182/blood-2006-12-064527. Epub 2007 Apr 20.
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.
在免疫系统中，细胞外ATP作为一种“天然佐剂”发挥作用，具有多种促炎效应。它由受损细胞释放，作为创伤和细胞死亡的指标，但可被CD39（核苷三磷酸二磷酸水解酶-1 [NTPDase 1]）灭活，CD39是一种将ATP降解为AMP的胞外酶。在此，我们表明CD39主要由免疫抑制性Foxp3(+)调节性T（Treg）细胞表达。在小鼠中，该酶几乎存在于所有CD4(+)CD25(+)细胞上。CD39的表达由Treg特异性转录因子Foxp3驱动，其催化活性因T细胞受体（TCR）连接而强烈增强。因此，活化的Treg细胞能够消除与ATP相关的效应，如P2受体介导的细胞毒性和ATP驱动的树突状细胞成熟。此外，人类Treg细胞表达CD39。与小鼠不同，人类中的CD39表达仅限于Foxp3(+)调节效应/记忆样T（T(REM)）细胞的一个亚群。值得注意的是，复发缓解型多发性硬化症（MS）患者血液中CD39(+) Treg细胞数量显著减少。因此，在人类中，CD39是一个可能参与控制炎症性自身免疫疾病的Treg亚群的标志物。
