Natural Killer T-cells (NKT cells) are a growing area of preclinical and clinical research, and modulation of these cells has therapeutic applications in various diseases with immunological, infectious, or oncologic components.

DESCRIPTION:

Investigators at UCSF and Harvard have identified, isolated, purified, and characterized a novel chemical composition – a glycolipid molecule, from a prominent commensal bacterium. The glycolipid is an analog of a known synthetic class of compounds that are known to activate natural killer T-cells. This new glycolipid compound is also a close analog of a previous clinical candidate for cancer and viral infections, and a current clinical candidate for autoimmune disorders, including graft-versus-host disease. However, the other known NKT activators are synthetic and are thus non-physiological. By contrast the new glycolipid is a fully natural glycolipid produced by resident microbes of the human GI tract.

The investigators have demonstrated the ability of the new glycolipid to activate NKT cells and classical NKT-cell cytokine response in cellular experiments (via administration to immune cells) and in vivo (via application of glycolipid-pulsed dendritic cells to conventional mice, and variable expression of the relevant synthetic pathway in gnotobiotic mice). 

Interestingly, the glycolipid appears to have a subtle but significant difference in in vitro affinity for NKT cells as well as a different cytokine activation profile from known, synthetic NKT activator. Our study implies that the co-evolved human gut microbiome might specifically produce this physiological glycolipid as a natural ligand that modulates the NKT subset of immune cells relevant to pathogen response and autoimmune disease. Given that the compound is significantly different in structure and activity than the previously studied compounds, this new glycolipid and the surrounding chemical space should be useful as therapeutics as well as research tools.