The gut microbiome consists of numerous symbiotic microbes, which play a role in host’s T cell mediated immune response. Of which, Bacteroides fragilis (B. fragilis), a prominent gut symbiont, produces glycosphingolipids, that could be presented by the antigen presenting molecule CD1d, leading to the subsequent activation of Natural Killer T (NKT) cells. This interaction between CD1d, gut lipids and NKT cells promotes mucosal healing, enhances epithelial barrier function, and restores immune homeostasis in gut-related disorders. To date, there are only two crystal structures which show how these B. fragilis produced glycosphingolipids (BfaGCs) are recognized by the NKT TCR. In this study, using X-ray crystallography, we report that BfaGCs are CD1d presented sphingolipids and the NKT TCR adopts a parallel mode of docking atop the CD1d-BfaGC complex.
Interestingly, we have found that there are specific interactions mediated between the BfaGCs and CD1d despite the observed universal parallel docking topology adopted by the NKT TCR. These findings provide molecular insights on novel CD1d presented lipids, which play a role in regulating the immunomodulatory role of the NKT cells in the gut. Affinity studies have further corroborated that CD1d-BfaGC complexes are tight binders for the NKT TCR, with nanomolar affinities. Overall, this study provides further insights on the symbiotic relationship between the host and the gut microbiota producing endogenous lipids, which serves as a promising new therapeutic approach for treating different infectious diseases, cancer and other autoimmune/inflammatory conditions.