Deletion of adenosine A2A receptor blocks the beneficial effects of Lactobacillus reuteri on Treg-deficiency-induced autoimmunity

Abstract

Abstract The lack of Foxp3+ regulatory T cells (Tregs) causes a lethal, CD4+T cell-driven autoimmune disease in scurfy (SF) mice and humans characterized by immunodysregulation, polyendocrinopathy, enteropathy, with X-linked inheritance (or IPEX syndrome). We observed that adenosine 2A receptor (A2A) activation limits inflammation and tissue damage, and that Lactobacillus reuteri DSM 17938 (LR) modulates the abnormal fecal microbial community associated with the disease, stimulating the production of bioactive metabolites, especially inosine by activating A2A expressed on T cells. To conclusively provide evidence of a central role of A2A in the actions of LR, we generated A2A null SF mice (SF·A2A−/−). Male mice were given daily by gavage culture media (MRS) or LR in MRS (107CFU/day), starting at d8 to d22 for plasma and tissue analysis or long-term survival We found that A2A receptor deletion in SF mice did not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of proinflammatory cytokines. LR treatment prolonged survival and reduced multi-organ inflammation in SF mice. In marked contrast, A2A receptor deletion reversed the effect of LR in prolonging lifespan in SF mice and negated the effects of LR on inflammation in the liver and lungs of SF mice. A2A deletion also inhibited LR-mediated reduction of TH1/TH2 cells and reversed the effect of LR on plasma pro-inflammatory cytokines. In conclusion, (a) the absence of the A2A receptor does not affect the development of disease in SF mice, and (b) the A2A receptor plays a critical role in immunomodulation produced by LR treatment. Lactobacillus reuteri and A2A receptor activation may have a role in other Treg dysfunction-mediated autoimmune diseases.