| CD39 (ENTPD1) is a prototypic ectonucleoside triphosphate diphosphohydrolase of the E‑NTPDase family that is anchored in the plasma membrane with two short transmembrane segments flanking a large extracellular catalytic loop, where it sequentially hydrolyzes extracellular nucleoside triphosphates and diphosphates, such as ATP and ADP, to AMP and thereby calibrates the magnitude, duration and chemical nature of purinergic signals in the vascular and immune systems. The extracellular domain contains the conserved apyrase signature motifs and metal‑binding residues that coordinate divalent cations and the γ‑ and β‑phosphates of ATP or ADP, allowing CD39 to remove two phosphate groups in successive steps and convert pro‑inflammatory, platelet‑activating ATP/ADP into AMP, which is subsequently dephosphorylated by the ecto‑5′‑nucleotidase CD73 to generate adenosine; in this way, CD39 functions as the rate‑limiting enzymatic step in the ATP→ADP→AMP→adenosine cascade. At the vascular interface, CD39 expressed on endothelial cells and platelets controls thromboregulation by hydrolyzing ATP and ADP in the extracellular space, blocking P2Y receptor–mediated platelet aggregation, limiting microvascular thrombosis and supporting blood flow, and genetic or pharmacologic disruption of CD39 activity increases susceptibility to thrombosis and ischemia–reperfusion injury, highlighting its importance for hemostatic balance. In immunity, CD39 is broadly expressed on B cells, dendritic cells, monocytes, macrophages, neutrophils, activated effector T cells and regulatory T cells, and its phosphohydrolytic activity shapes T‑cell activation, polarization and stability by scavenging pro‑inflammatory ATP released during inflammation, hypoxia or cell damage and facilitating the accumulation of immunosuppressive adenosine via CD73, thus shifting the environment from ATP‑driven P2 receptor signaling (calcium mobilization, chemotaxis, inflammasome activation) toward P1 receptor–mediated anti‑inflammatory signals. CD39 expression on conventional and regulatory T cells is dynamically regulated by cytokines and microenvironmental cues, and CD39⁺ Tregs show enhanced capacity to suppress effector responses in autoimmunity and transplantation through combined ATP degradation and adenosine generation, while high CD39 levels in inflamed tissues confer a competitive advantage for T‑cell–mediated immunoregulation where extracellular ATP concentrations are elevated. In cancer, CD39 is upregulated on intratumoral T cells, myeloid cells and sometimes tumor cells themselves, and reviews emphasize that CD39, together with CD73, drives the conversion of immunostimulatory ATP released by dying cells into immunosuppressive adenosine, establishing an adenosine‑rich tumor microenvironment that dampens cytotoxic T‑cell and NK‑cell function via A2A and A2B receptors and supports tumor progression; CD39 is therefore regarded as an immunological switch and emerging checkpoint target, with therapeutic blockade of CD39 proposed to enhance antitumor immunity by preserving ATP signaling and reducing adenosine accumulation. CD39 dysregulation has been linked to a spectrum of immune‑related disorders, including inflammatory bowel disease, sepsis, multiple sclerosis, allergic disease, systemic lupus erythematosus, diabetes and vascular inflammatory states, reflecting its central position at the crossroads between extracellular nucleotide metabolism, thrombosis and inflammation. |
