CD39

CD39, also known as ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), is a cell-surface enzyme that hydrolyzes extracellular ATP and ADP to AMP. It is a member of the ENTPD family and is a type II transmembrane protein with a large extracellular catalytic domain. The ENTPD1 gene encodes the protein. CD39 is broadly expressed, including on vascular endothelium, regulatory T cells, dendritic cells, macrophages, microglia, and platelets, where it participates in regulating purinergic signaling in tissues and the immune system.

Mechanistically, extracellular ATP and ADP act as danger signals that promote inflammation and platelet activation. CD39 rapidly dephosphorylates ATP and ADP to AMP, which is further dephosphorylated by CD73 to adenosine. Adenosine then signals through adenosine receptors (A1, A2A, A2B, A3) to modulate inflammation, vascular tone, and immune responses. By reducing ATP/ADP signaling and increasing adenosine, CD39 tends to dampen inflammatory reactions and influence thrombosis and immunity.

Functional roles of CD39 include regulation of inflammatory and thrombotic processes, and the promotion of immune tolerance in contexts such as transplantation and the tumor microenvironment. In regulatory T cells, CD39 serves as a phenotypic marker alongside CD25 and FOXP3. In cancer, elevated CD39 (often with CD73) can contribute to adenosine production that suppresses anti-tumor immunity.

CD39 is a focus of therapeutic interest, with research exploring recombinant CD39 to limit inflammation and thrombosis, and selective inhibitors (used mainly as research tools) such as ARL67156 and POM-1 to study ENTPD activity.