TLR9 stimulation by the gut microbiota promotes tissue-specific immunosuppression in autoimmune-prone MRL/lpr mice

Abstract

Abstract To investigate the ability of gut microbiota to modify immune regulation in autoimmune disease, we treated lupus-prone mice with oral vancomycin prior to disease development, and subsequently administered bacterial DNA isolated from commensal bacteria. Vancomycin given prior to disease initiation promotes exacerbation of autoimmune disease, likely due to a decrease in the frequency of B regulatory (Breg) cells, whereas vancomycin given after autoimmune disease onset has suppressive effects on disease phenotype in MRL/lpr mice. Bacterial DNA administration during the pre-disease stage promoted Breg cell production and suppressed autoimmune disease parameters in MRL/lpr mice. Further, we showed that activation of toll-like receptor 9 (TLR9) on B cells was involved in the suppressive effects of bacterial DNA seen in the MRL/lpr mouse model. We found that during the pre-disease period, joint treatment with vancomycin and oral administration of a TLR9 specific agonist, ODN 1826, promoted Breg cells in the lamina propria, increased total CD8+ T cells and effector memory CD44 expressingCD8+ T cells in the spleen, and suppressed Th17 and IFNγ producing CD4+ T cells in the mesenteric lymph nodes. Oral ODN 1826 administration also increased the Treg/Th17 ratio in the mesenteric lymph nodes. The alterations in suppressive vs. proinflammatory cell phenotypes by oral exposure to ODN 1826 suggests that the suppressive effects of bacterial DNA from the gut microbiota are modulated through TLR9 activation in a tissue-specific manner.