Augmented Th17-stimulating activity of BMDCs as a result of reciprocal interaction between γδ and dendritic cells.

Our previous studies demonstrated that γδ T cells have a strong regulatory effect on Th17 autoimmune responses in experimental autoimmune uveitis (EAU). In the current study, we show that reciprocal interactions between mouse γδ T cells and dendritic cells (DCs) played a major role in γδ regulation of Th17 responses. Mouse bone marrow-derived dendritic cells (BMDCs) acquired an increased ability to enhance Th17 autoimmune responses after exposure to γδ T cells; meanwhile, after exposure, a significant portion of the BMDCs expressed CD73 - a molecule that is fundamental in the conversion of immunostimulatory ATP into immunosuppressive adenosine. Functional studies showed that CD73 BMDCs were uniquely effective in stimulating the Th17 responses, as compared to CD73 BMDCs; and activated γδ T cells are much more effective than non-activated γδ T cells at inducing CD73 BMDCs. As a result, activated γδ T cells acquired greater Th17-enhancing activity. Treatment of BMDCs with the CD73-specific antagonist APCP abolished the enhancing effect of the BMDCs. γδ T cells more effectively induced CD73 BMDCs from the BMDCs that were pre-exposed to TLR ligands, and the response was further augmented by adenosine. Moreover, BMDCs acquired increased ability to stimulate γδ activation after pre-exposure to TLR ligands and adenosine. Our results demonstrated that both extra-cellular adenosine and TLR ligands are critical factors in augmented Th17 responses in this autoimmune disease, and the reciprocal interactions between γδ T cells and DCs play a major role in promoting Th17 responses.