Inhibition of cGAS in dendritic cells suppresses maturation and prolongs allograft survival in mice

Abstract Background Dendritic cells (DCs) regulate immune responses. Recent studies show that cyclic GMP-AMP synthase (cGAS) plays a crucial role in DC maturation. This study investigates the effect of suppressing cGAS expression in DCs on graft immune tolerance. Methods Bioinformatics analysis was conducted to explore the potential role of cGAS in transplant immunity. Immature dendritic cells (imDCs) were isolated, purified, and transduced with an adenovirus vector to suppress cGAS expression.EGFP-DCs group, cGAS-shRNA-DCs group, and control group(PBS), were injected via the tail vein prior to skin and islet transplantation for the establishment of a mouse transplantation model.Analyze graft survival and pathological changes, and use flow cytometry to assess spleen T cell subset proportions. After lipopolysaccharide stimulation, evaluate MHC-II and co-stimulatory molecule expression, antigen phagocytosis, and T cell proliferation in the imDCs (control), EGFP-DCs, and cGAS-shRNA-DCs groups. The supernatants from every group were collected, and the changes in cytokine secretion by DCs were detected using ELISA. Results Bioinformatics analysis shows increased cGAS expression in the allograft group. The cGAS-shRNA-DCs group showed reduced MHC-II and co-stimulatory molecule expression, enhanced phagocytic activity, and decreased T cell activation ability. Levels of IFN-γ, IL-1β, TNF-α, and IL-6 were lower, while IL-10 levels were higher. Mice receiving cGAS-shRNA-DCs had prolonged graft survival and improved graft function. Flow cytometry revealed an increased proportion of regulatory T cells and reduced Th1 and Th17 cell populations. Conclusions Inhibiting cGAS expression in DCs reduces their maturation, antigen-presenting capacity, and T-cell activation, ultimately prolonging graft survival.