The microbiome regulates the homeostasis of host invariant natural killer T (iNKT) cells (MUC4P.830)

Symbiotic bacteria intimately participate in host physiological processes and impact host health and disease, although details at the molecular level largely remain unknown. We discovered that symbiotic Bacteroides species produce sphingolipids to modify the host antigen environment of the invariant natural killer T (iNKT) cells, a key immune modulator recognizing CD1d-restricted lipids. Using gnotobiotic technology and analytical tools, we found that bacterial glycosphingolipids, specifically one molecular fraction called GSL-Bf717, block iNKT cell activation and inhibit cell proliferation in early life. As a result, the total colonic iNKT cell number is restricted in adulthood and the host is protected when challenged by iNKT cell-mediated oxazolone colitis. These results suggest that intestinal bacterial sphingolipids are critical for establishing colonic iNKT cell homeostasis and host tolerance to environmental challenges. In addition, we find that the regulation depends on exposure to these symbiotic molecules in a critical early-life window, which, if missed, has irreversible impacts on host. This study contributes to our understanding of the essential role microbes play in host health and disease with precious molecular details that are largely lacking. The unique inhibitive power of GSL-Bf717 can be harnessed to provide therapeutic interventions in human autoimmune and allergic disorders where iNKT cell activation is detrimental.