Production of an NKT cell stimulatory glycosphingolipid by a prominent member of the human gut microbiota (55.22)

Abstract

Abstract While the human gut microbiota are suspected to produce diffusible small molecules that modulate host signaling pathways, few of these molecules have been identified. Species of Bacteroides and their relatives, which often comprise >50% of the gut community, are unusual among bacteria in that their membrane is rich in sphingolipids, a class of signaling molecules that play a key role in modulating the host immune response. Although known for more than three decades, the full repertoire of Bacteroides sphingolipids has not been defined or linked to immune modulatory activity. We report that Bacteroides fragilis produces the glycosphingolipid α-galactosylceramide (α-GalCerBf), which is structurally related to a sponge-derived glycosphingolipid (α-GalCer, KRN7000) that is the prototypical agonist of CD1d-restricted natural killer T (NKT) cells. We demonstrate that α-GalCerBf binds to CD1d and stimulates the production of cytokines by both mouse and human NKT cells. In vivo, we show that α-GalCerBf stimulates NKT cells to induce the activation markers CD25 and CD69, secrete IFN-γ in a CD1d-dependent manner and can prevent cyclophosphamide-induced diabetes. These data suggest that NKT cells directly sense an endogenous antigen produced by a prominent human gut symbiont, uncovering a new mechanism by which the gut microbiota modulate a subset of immune cells relevant to pathogen response and autoimmune disease.