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.