The CD39 gene codes for an enzyme known as CD39, or ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1). This enzyme resides on the surface of various cells throughout the body, notably on immune and endothelial cells. CD39 plays an important role in regulating extracellular nucleotides, which are signaling molecules that operate outside of cells.
Understanding CD39’s Cellular Function
CD39 functions as an ectonucleotidase, breaking down nucleotides in the extracellular space. It hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP). This enzymatic activity is important because ATP and ADP are signaling molecules involved in purinergic signaling.
Purinergic signaling is a widespread communication system where extracellular nucleotides like ATP and ADP bind to specific receptors on cell surfaces to trigger various cellular responses. By converting ATP and ADP to AMP, CD39 reduces the levels of these signals. This regulation is involved in numerous cellular activities, including inflammation, blood clotting, and nerve function.
CD39’s Role in Immune System Balance
CD39’s enzymatic activity impacts the immune system by modulating the balance between pro-inflammatory and anti-inflammatory signals. By breaking down pro-inflammatory ATP and ADP into AMP, CD39 leads to the production of adenosine. AMP is then converted into adenosine by the enzyme CD73. Adenosine, in contrast to ATP and ADP, is an immunosuppressive molecule.
This conversion pathway, often referred to as the CD39/CD73 pathway, is expressed on various immune cells, including regulatory T cells (Tregs), myeloid cells, and natural killer (NK) cells. On Tregs, CD39 activity is important for their immunosuppressive function, as it facilitates the local generation of adenosine. This adenosine then acts on other immune cells to dampen immune responses. This mechanism helps resolve inflammation and maintain immune tolerance, preventing the immune system from attacking the body’s own tissues.
CD39 and Human Health Conditions
Dysregulation of CD39 activity or expression is linked to various human health conditions. In cancer, elevated CD39 expression in the tumor microenvironment can suppress anti-tumor immunity. By depleting pro-inflammatory ATP and increasing immunosuppressive adenosine, CD39 can shield tumor cells from immune attack, promoting tumor growth and progression.
CD39 is also connected to autoimmune diseases, where its malfunction can disrupt immune tolerance. Alterations in CD39 expression on regulatory T cells have been observed in conditions such as rheumatoid arthritis and systemic lupus erythematosus. Furthermore, CD39 plays a role in cardiovascular diseases by influencing platelet aggregation and vascular inflammation. Its activity helps prevent excessive blood clot formation and supports healthy blood flow.
Therapeutic Potential of CD39
Understanding CD39’s roles in health and disease has opened avenues for therapeutic intervention. Strategies targeting CD39 involve inhibiting its enzymatic activity, particularly in cancer, to enhance anti-tumor immunity. By blocking CD39, researchers aim to prevent immunosuppressive adenosine accumulation and increase extracellular ATP, which activates anti-tumor immune responses.
Current research explores various approaches, including small molecule inhibitors and monoclonal antibodies that specifically target CD39. Monoclonal antibodies against CD39 are in clinical trials to assess their ability to restore immune function in cancer patients. These therapies are being investigated in combination with existing immune checkpoint inhibitors, such as PD-1/PD-L1 blockers, to achieve a stronger anti-cancer effect.