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α-Glucuronosyl and α-Glucosyl Diacylglycerides, Natural Killer T Cell-Activating Lipids from Bacteria and Fungi

submitted on 15.10.2019, 21:14 and posted on 21.10.2019, 16:52 by SATVIKA BURUGUPALLI, CATARINA DOS SANTOS SA E ALMEIDA, Dylan GM Smith, SAYALI SHAH, ONISHA PATEL, Jamie Rossjohn, ADAM ULDRICH, DALE GODFREY, Spencer Williams
Natural killer T cells express T cell receptors (TCRs) that recognize glycolipid antigens in association with the antigen-presenting molecule CD1d. Here, we report the concise chemical synthesis of a range of saturated and unsaturated α-glucosyl and α-glucuronosyl diacylglycerides of bacterial and fungal origins from allyl α-glucoside with Jacobsen kinetic resolution as a key step. We show that these glycolipids could be recognized by a classical type I NKT TCR that uses an invariant Vα14-Jα18 TCR α-chain, but also by an atypical NKT TCR that uses a different TCR α-chain (Vα10-Jα50). In both cases, recognition was sensitive to the lipid fine structure, and included recognition of glycosyl diacylglycerides bearing branched (R- and S-tuberculostearic acid) and unsaturated (oleic and vaccenic) acids. The TCR footprints on CD1d-loaded with a mycobacterial α-glucuronosyl diacylglyceride was assessed using mutant CD1d molecules and, while similar to that for α-GalCer recognition by a type I NKT TCR, were more sensitive to mutations when α-glucuronosyl diacylglyceride was the antigen. In summary, we provide an efficient approach for synthesis of a broad class of bacterial and fungal α-glycosyl diacylglyceride antigens and demonstrate that they can be recognised by TCRs derived from type I and atypical NKT cells.


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Unravelling the immunology of complex glycolipids by chemical synthesis

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ARC Centre of Excellence in Advanced Molecular Imaging

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Email Address of Submitting Author


University of Melbourne



ORCID For Submitting Author


Declaration of Conflict of Interest

D.I.G. is a member of the scientific advisory board of Avalia Immunotherapies, a company working on NKT cell-based vaccines. The other authors declare no conflicts of interest.

Version Notes

Version 1.0