Generation and Function of Non-cell-bound CD73 in Inflammation

Abstract

Extracellular adenine nucleotides participate in cell-to-cell communication and modulate the immune response. The concerted action of ectonucleotidases CD39 and CD73 plays a major role in the local production of anti-inflammatory adenosine, but both ectonucleotidases are rarely co-expressed by human T cells. The expression of CD39 on T cells increases upon T cell activation and is high at sites of inflammation. CD73, in contrast, disappears from the cellular membrane after activation. The possibility that CD73 could act in trans would resolve the conundrum of both enzymes being co-expressed for the degradation of ATP and the generation of adenosine. An enzymatically active soluble form of CD73 has been reported, and AMPase activity has been detected in body fluids of patients with inflammation and cancer. It is not yet clear how CD73, a glycosylphosphatidylinositol (GPI)-anchored protein, is released from the cell membrane, but plausible mechanisms include cleavage by metalloproteinases and shedding mediated by cell-associated phospholipases. Importantly, like many other GPI-anchored proteins, CD73 at the cell membrane is preferentially localized in detergent-resistant domains or lipid rafts, which often contribute to extracellular vesicles (EVs). Indeed, CD73-containing vesicles of different size and origin and with immunomodulatory function have been found in the tumor microenvironment. The occurrence of CD73 as non-cell-bound molecule widens the range of action of this enzyme at sites of inflammation. In this review, we will discuss the generation of non-cell-bound CD73 and its physiological role in inflammation.

Defining the CD39/CD73 Axis in SARS-CoV-2 Infection: The CD73- Phenotype Identifies Polyfunctional Cytotoxic Lymphocytes

“…Despite their complementary function, CD39 and CD73 are rarely co-expressed on peripheral human lymphocytes (with the exception of B cells) [19]. In humans, CD73 is generally expressed on endothelial cells, B cells, naïve CD8 + T cells, and a subset of memory CD4 + T cells [20]. Recent studies show that upon activation, CD73 may be shed from the cell surface resulting in a disturbance of ATP/ADO balance in the extracellular matrix (ECM) [20,21].…”

“…In humans, CD73 is generally expressed on endothelial cells, B cells, naïve CD8 + T cells, and a subset of memory CD4 + T cells [20]. Recent studies show that upon activation, CD73 may be shed from the cell surface resulting in a disturbance of ATP/ADO balance in the extracellular matrix (ECM) [20,21]. In fact, cells that lose CD73 could be protected by pericellular ADO, thus maintaining their effector function [20].…”

“…Recent studies show that upon activation, CD73 may be shed from the cell surface resulting in a disturbance of ATP/ADO balance in the extracellular matrix (ECM) [20,21]. In fact, cells that lose CD73 could be protected by pericellular ADO, thus maintaining their effector function [20]. A specific mechanism for the observed loss of CD73 on cytotoxic lymphocytes in COVID-19 remains to be elucidated.…”

Decreased Equilibrative Nucleoside Transporter 1 (ENT1) Activity Contributes to the High Extracellular Adenosine Levels in Mesenchymal Glioblastoma Stem-Like Cells

“…Based on their Km values (PAP: 0.37–2 mM: CD73: 24 µM) using AMP as a substrate [ 61 , 62 , 63 ], a preponderant role of CD73 could be conjectured around the formation of adenosine over PAP. Further, it has been suggested that the conversion of AMP to adenosine may be produced by CD73 and, less efficiently, by alkaline phosphatase (PAP) [ 64 ]. However, the acidification of the tumor microenvironment caused by lactic acid which is secreted from cancer cells could lead to disturbances around the activity of the proteins in question [ 65 , 66 , 67 ].…”

Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy

“…These results rule out any relevant CD39 activity in serum of patients with melanoma, according to previous reports showing that ATPase and ADPase activities in human blood are mainly mediated by cell-bound enzymes. 19 Expression of CD39 was also evaluated in serum samples from healthy subjects (n=10) and patients with melanoma (n=31). No difference was observed in CD39 expression between the two groups (online supplemental figure 2b).…”