Abstract
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 γδ T cells expressed the highest levels of A2AR mRNA and that A2AR ligation inhibited αβ T cell activation, but enhanced γδ 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 γδ T cells. Furthermore, compared to resting cells, activated γδ 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+ γδ T cells, and this effect was abolished by a CD73 inhibitor. Our results show that expression of increased amounts of A2AR allows γδ 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 γδ T cells to acquire increased proinflammatory activity, leading to augmented autoimmune responses.
Highlights
Adenosine accumulates at inflamed sites as a result of release of adenosine triphosphate (ATP) into the extracellular environment, its subsequent dephosphorylation to adenosine diphosphate (ADP) and adenosine monophosphate (AMP), and a terminal reaction in which AMP is converted to adenosine [1,2]
The percentage of proliferating CFSE-labeled interphotoreceptor retinoid-binding protein (IRBP)-specific T cells was significantly decreased by NECA (Fig. 1A and B) and this effect was inhibited by the selective A2A receptor (A2AR) antagonist, but not the A2BR antagonist (Fig. 1A and B), indicating that the suppressive effect was due to ligation of the A2AR
We assessed the effect of NECA on cd T cell activation. cd T cells were prepared from immunized B6 mice, rested for a few days by culture in cytokine-free medium [19,20,21], tested for activation by cytokines in the presence or absence of NECA with or without the A2AR or A2BR antagonist
Summary
Adenosine accumulates at inflamed sites as a result of release of adenosine triphosphate (ATP) into the extracellular environment, its subsequent dephosphorylation to adenosine diphosphate (ADP) and adenosine monophosphate (AMP), and a terminal reaction in which AMP is converted to adenosine [1,2]. Adenosine release in damaged tissues decreases the energy demand of the tissue by exerting a direct inhibitory effect on parenchymal cell function [1,3,4]. It reduces the local inflammatory response and modulates various immune responses [5,6,7]. Release of adenosine and its binding to adenosine receptors (ARs) on immune cells represents a potent endogenous immunosuppressive pathway that regulates the immune response to harmful external insults [8]. A proinflammatory effect of adenosine has been recognized [12,13,14]
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