Symbionts Exploit Complex Signaling to Educate the Immune System

The mammalian immune system is tolerized to trillions of microbes residing on bodily surfaces and can discriminate between symbionts and pathogens despite their having related microbial structures. Mechanisms of innate immune activation and the subsequent signaling pathways used by symbionts to communicate with the adaptive immune system are poorly understood. Polysaccharide A (PSA) of Bacteroides fragilis is the model symbiotic immunomodulatory molecule. Here we demonstrate that PSA-dependent immunomodulation requires the TLR2/TLR1 heterodimer in cooperation with Dectin-1 to initiate signaling by the downstream PI3K pathway, with consequent CREB-dependent transcription of anti-inflammatory genes including antigen presentation and co-signaling molecules. High-resolution LC-MS/MS analysis of PSA identified a previously unknown small-molecular-weight, covalently attached bacterial outer membrane–associated lipid that is required for activation of antigen-presenting cells. This archetypical commensal microbial molecule initiates a complex collaborative integration of TLR and C-type lectin–like receptor signaling mechanisms culminating in the activation of the anti-inflammatory arm of the PI3K pathway that serves to educate CD4+ Tregs to produce the immunomodulatory cytokine interleukin 10. Immunomodulation is a key function of the microbiome and is a focal point for developing new therapeutic agents.