Microbes talk to T cells

PLoS Biol. 11, e1001610 (2013)

Sphingolipids are signaling molecules that are prevalent in eukaryotes but infrequent in bacteria. One exception is the prevalent gut microbe, Bacteroides fragilis, in which sphingolipids are abundant in the membrane. To learn more about these sphingolipids and their potential roles in host biology, Brown et al. first searched for enzymes involved in sphingolipid biosynthesis. Knockout of BF2461, anticipated to serve as the first committed step in sphingolipid biosynthesis, resulted in the loss of three sphingolipids as compared to the wild-type strain, one of which was an unknown species. MS and NMR characterization, as well as comparison with a synthetic standard, defined the new species as an α-galactosylceramide named α-GalCel_Bf. The only other known naturally occurring α-galactosylceramides are the sponge-derived agelasphins, with the synthetic natural killer T (NKT) cell agonist KRN7000 derived from agelasphin-9b. Given this structural similarity, the authors tested whether α-GalCel_Bf might similarly have a role in immune signaling. α-GalCel_Bf was shown to bind the host immune receptor CD1d and to stimulate mouse and human NKT cells. NKT cells isolated from mice immunized with purified α-GalCel_Bf also showed signs of activation. Tests of germ-free and specific pathogen–free mice colonized with wild-type and DBF2461 B. fragilis were inconclusive given variations in NKT cell numbers, but the high prevalence of both B. fragilis and its sphingolipid components in the human gut suggest that α-GalCel_Bf could serve as the endogenous complement to KRN7000.