Adenosine receptor ligation tips the uveitogenic Th1 and Th17 balance towards the latter in experimental autoimmune uveitis-induced mouse

Various pathological conditions are accompanied by release of adenosine triphosphate (ATP) from the intracellular to the extracellular compartment, where it degrades into adenosine and modulates immune responses. Previous studies concluded that both ATP and its degradation product adenosine are important immune-regulatory molecules; ATP acted as a danger signal that promotes immune responses, but adenosine's effect was inhibitory. We show that adenosine receptor ligation plays an important role in balancing Th1 and Th17 pathogenic T cell responses in experimental autoimmune uveitis (EAU). While its effect on Th1 responses is inhibitory, its effect on Th17 responses is enhancing, thereby impacting the balance between Th1 and Th17 responses. Mechanistic studies showed that this effect is mediated via several immune cells, among which γδ T cell activation and dendritic cell differentiation are prominent; adenosine- and γδ-mediated immunoregulation synergistically impact each other's effect. Adenosine receptor ligation augments the activation of γδ T cells, which is an important promoter for Th17 responses and has a strong effect on dendritic cell (DC) differentiation, tipping the balance from generation of DCs that stimulate Th1 responses to those that stimulate Th17 responses. The knowledge acquired in this study should improve our understanding of the immune-regulatory effect of extracellular ATP-adenosine metabolism and improve treatment for autoimmune diseases caused by both Th1- and Th17-type pathogenic T cells.