Roles of the Adenosine Receptor and CD73 in the Regulatory Effect of γδ T Cells

The adenosine A2A receptor (A2AR), the main functional adenosine receptor on murine T cells, plays a unique role in the attenuation of inflammation and tissue damage in vivo. Here, we showed that, of the immune cell types tested, activated gamma delta T cells expressed the highest levels of A2AR mRNA and that A2AR ligation inhibited alpha beta T cell activation, but enhanced gamma delta T cell activation. We also showed that the inhibitory effect of an adenosine receptor agonist on autoreactive T cells was prevented by addition of a low percentage of activated gamma delta T cells. Furthermore, compared to resting cells, activated gamma delta T cells expressed significantly lower levels of CD73, an enzyme involved in the generation of extracellular adenosine. Exogenous AMP had a significant inhibitory effect on autoreactive T cell responses, but only in the presence of CD73(+) gamma delta T cells, and this effect was abolished by a CD73 inhibitor. Our results show that expression of increased amounts of A2AR allows gamma delta T cells to bind adenosine and thereby attenuate its suppressive effect, while decreased expression of CD73 results in less generation of adenosine in the inflammatory site. Together, these events allow activated gamma delta T cells to acquire increased proinflammatory activity, leading to augmented autoimmune responses.