To the editor:

We read with interest the recent article by Borsellino and colleagues on the role of CD39 and CD73 for the suppressor activity of Foxp3+ regulatory T cells (T regs).1 

Because the major sources of extracellular ATP are injured cells leaking cytoplasmic content, degranulating platelets, and endothelial cells under shear stress, extracellular ATP may represent a constitutive endogenous molecule that signals tissue stress and injury. Borsellino and colleagues proposed that the immune suppressive activity of T regs is due, at least in part, to their capacity to remove ATP from the extracellular space through the enzymatic activity of CD39 and CD73 expressed on their membrane.

It has been recently shown that T regs exert immune suppression by elevating intracellular cyclic AMP (cAMP) concentration in target cells.2  As suggested by Borsellino and others, T regs might do so by degrading ATP to adenosine. In turn, adenosine activates adenylyl cyclases by triggering the cognate Gs-protein coupled receptor A2a.1,3  However we would like to point out that in human cells ATP can act as a direct cAMP-elevating agent thus delivering a potent anti-inflammatory signal. This is because human, but not murine, cells express the purinergic receptor P2Y11 that is the only P2 purinergic receptor coupled to adenylyl cyclases activation.4 

Cells expressing P2Y11 include dendritic cells (DCs), macrophages, T lymphocytes, and natural killer cells. Human DCs- exposed to micromolar concentrations of extracellular ATP do not undergo “classic” maturation. In fact, although ATP-stimulated DCs up-regulate costimulatory membrane molecules, they also display blocked pro-inflammatory cytokine and chemokine production including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-12, CCL2, CCL3, CCL5, and CXCL10, while IL-10 and IL1Ra are either unaffected or up-regulated.5,7  Moreover, extracellular ATP induces DCs to produce large amounts of Thrombospondin-1 and synergyzes with interferon-γ (IFN-γ) in up-regulating indoleamine 2,3 dioxygenase, turning DCs into tolerogenic antigen presenting cells.8  These effects are mimicked by the nonhydrolyzable ATP analog ATP-γ-S and by several cyclic AMP elevating agents, as well as by the administration of cell permeable cAMP analogs.8,9  Moreover, extracellular ATP has proven able to inhibit T lymphocyte and NK cell proliferation and cytokine production as well as NK-mediated cytotoxicity, associated with increased intracellular cAMP concentration.10 

Extracellular ATP released from injured cells might not act as an activating danger signal but it might rather represent a negative feedback for immune cells to limit self-harmful excessive inflammation in the context of extensively damaged human tissues. This view suggests that extracellular ATP hydrolysis operated by human CD39+ T regs might have more complex physiologic consequences than blunt immune suppression.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Andrea la Sala, Laboratory of Molecular and Cellular Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Via dei Bonacolsi, 81, 00163 Rome, Italy; e-mail: [email protected].

1
Borsellino
G
Kleinewietfeld
M
Di Mitri
D
et al
Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.
Blood
2007
110
1225
1232
2
Bopp
T
Becker
C
Klein
M
et al
Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression.
J Exp Med
2007
204
1303
1310
3
Deaglio
S
Dwyer
KM
Gao
W
et al
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.
J Exp Med
2007
204
1257
1265
4
Abbracchio
MP
Burnstock
G
Boeynaems
JM
et al
International Union of Pharmacology LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy.
Pharmacol Rev
2006
58
281
341
5
la Sala
A
Ferrari
D
Corinti
S
et al
Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses.
J Immunol
2001
166
1611
1617
6
la Sala
A
Sebastiani
S
Ferrari
D
et al
Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes.
Blood
2002
99
1715
1722
7
Horckmans
M
Marcet
B
Marteau
F
et al
Extracellular adenine nucleotides inhibit the release of major monocyte recruiters by human monocyte-derived dendritic cells.
FEBS Lett
2006
580
747
754
8
Marteau
F
Gonzalez
NS
Communi
D
et al
Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells.
Blood
2005
106
3860
3866
9
Ferrari
D
Gorini
S
Callegari
G
la Sala
A
Shaping immune responses through the activation of dendritic cells' P2 receptors.
Purinergic Signal
2007
3
99
107
10
Miller
JS
Cervenka
T
Lund
J
Okazaki
IJ
Moss
J
Purine metabolites suppress proliferation of human NK cells through a lineage-specific purine receptor.
J Immunol
1999
162
7376
7382
Sign in via your Institution