Dennis Kasper

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA USA

The host immune system and the microbiota interact constantly. To date, we have discovered the only bacterial structures from the gut flora known to stimulate the immune system during commensalism. We have delineated the innate and adaptive cellular mechanisms governing the physiologic immunoregulatory processes stimulated by polysaccharide A (PSA) of Bacteroides fragilis. Immunoregulation by this single bacterial molecule from a commensal organism requires plasmacytoid dendritic cells (PDCs) to induce regulatory T cells. Overturning immunologic paradigms, this zwitterionic polysaccharide was found to be processed and presented by major histocompatibility class II molecules. PSA plays an essential role in shaping mammalian immune development and displays potent immunomodulatory and anti-inflammatory activity, stimulating CD4+ T-cell production of interleukin 10, which protects mice against experimental inflammatory bowel disease and experimental allergic encephalitis. Recognition of gut microbial products by the host’s immune cells establishes gut homeostasis and depends on both the innate and adaptive arms of the immune system. In Gram-negative bacteria, capsular polysaccharides play a crucial role in the colonization, virulence, and fitness of the organisms and in their interaction with the physical environment and the host’s immune system. The hydrophilic capsular polysaccharides are most commonly anchored to the outer membrane by covalently bound lipid moieties at the reducing end of the polysaccharide. We have defined the structure of the lipid terminus of PSA and demonstrated a key role for this lipid in activation of the innate immune system. Natural molecules like PSA have very complex signaling mechanisms to the immune system.