Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.
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.
Borsellino
Giovanna
G
Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy.
Kleinewietfeld
Markus
M
Di Mitri
Diletta
D
Sternjak
Alexander
A
Diamantini
Adamo
A
Giometto
Raffaella
R
Höpner
Sabine
S
Centonze
Diego
D
Bernardi
Giorgio
G
Dell'Acqua
Maria Luisa
ML
Rossini
Paolo Maria
PM
Battistini
Luca
L
Rötzschke
Olaf
O
Falk
Kirsten
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen