Hydrolysis of extracellular ATP and immune suppression: humans versus mice

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.