The cAMP–Adenosine Feedback Loop Maintains the Suppressive Function of Regulatory T Cells

Therapeutic manipulation of regulatory T cells (Tregs) has been regarded as a promising approach for the treatment of immune disorders. However, a better understanding of the immunomodulatory mechanisms of Tregs and new safe and effective methods to improve the therapeutic effects of Tregs are highly desired. In this study, we have identified the key roles of a cAMP-adenosine positive feedback loop in the immunomodulatory function of Tregs. Adult male C57BL/6J mice were used for an experimental autoimmune uveitis (EAU) model, Tregs, and uveitogenic T cells (UTs). In established EAU, induced Tregs (iTregs) administration alleviated the inflammatory response. In vitro, iTregs inhibited UTs proliferation and inflammatory cytokine production. Mechanistically, cAMP is partially responsible for iTreg-mediated inhibition on UTs. Importantly, intracellular cAMP regulates CD39 expression and CD39-dependent adenosine production in iTregs, and cAMP directly participates in iTreg-derived adenosine production by a CD39 signaling-independent extracellular cAMP-adenosine pathway. Moreover, extracellular adenosine increases the intracellular cAMP level in Tregs. More importantly, increasing the cAMP level in iTregs before transfer improves their therapeutic efficacy in established EAU. Notably, the cAMP-adenosine loop exists in both iTregs and naturally occurring Tregs. These findings provide new insights into the immunosuppressive mechanisms of Tregs and suggest a new strategy for improving the therapeutic efficacy of Tregs in established autoimmune disease.