CD39 and CD73 in immunity and inflammation

Abstract

The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders.

Figure 1

CD39 and CD73 shape the “purinergic halo” surrounding immune cells. The occurrence of pathological events, such as inflammation, promotes a massive accumulation of ATP, which serves as a key “danger” signal, triggering a series of proinflammatory responses (a). However, negative feedback also takes part in this context because the increased ATP secretion, as observed in the early phase of inflammation, is followed by its sequential degradation to AMP by CD39, and to adenosine by CD73. Adenosine promotes a depressive action on the immune cell activity and exerts a potent anti-inflammatory effect (b). Abbreviations: ADO, adenosine; GPI, glycosylphosphatidyl inositol.

Figure 2

The CD39/CD73 pathway modulates Treg activity. The activation of T cell receptor (TCR), expressed on Tregs, induces CD39 activity. This increment of ATP-metabolizing activity is critical for the immunosuppressive activity of Tregs because it facilitates the pericellular generation of adenosine, a substantial component of the immunosuppressive and anti-inflammatory functions of Treg cells. The inhibitory action of Treg-derived adenosine can be ascribed to the activation of A_2A receptors expressed on T effector cells, which undergo reduced immune activity. In addition, adenosine generation triggers a self-reinforcing loop of Treg functions because the stimulation of A_2A receptors, expressed on these cells, elicits their expansion and increases their immunoregulatory activity. Abbreviations: GPI, glycosylphosphatidyl inositol; TCR, T cell receptor.

Figure 3

The CD39/CD73 axis in neoplastic development and progression. Within the tumor environment, ATP is released and is converted into adenosine by upregulated CD39 and CD73. Adenosine promotes cancer growth by acting directly on neoplastic cells through A₁, A_2A, A_2B, and/or A₃ adenosine receptor activation and by subsequent enhancement of invasiveness and metastatic ability. The engagement of A_2A and A_2B receptors on endothelial cells enhances the production of pro-angiogenic factors (β-FGF, VEGF and IL-8). In addition, the adenosine generated by CD39/CD73 expressed either on primary neoplastic cells or on cancer exosomes generates an immunosuppressive environment by acting on macrophages, neutrophils, dendritic cells and T cells. Abbreviations: IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; VEGF, vascular endothelial growth factor; β-FGF, fibroblast growth