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α-Glucuronosyl and α-glucosyl diacylglycerides, natural killer T cell-activating lipids from bacteria and fungi

Abstract

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. These glycolipids are recognized by a classical type I NKT TCR that uses an invariant Vα14-Jα18 TCR a-chain, but also by an atypical NKT TCR that uses a different TCR α-chain (Vα10-Jα50). In both cases, recognition is sensitive to the lipid fine structure, and includes 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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Supplementary files

Article information


Submitted
17 Oct 2019
Accepted
09 Jan 2020
First published
14 Jan 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Accepted Manuscript
Article type
Edge Article

α-Glucuronosyl and α-glucosyl diacylglycerides, natural killer T cell-activating lipids from bacteria and fungi

S. S. Burugupalli, C. F. Almeida, D. G. Smith, S. Shah, O. Patel, J. Rossjohn, A. P. Uldrich, D. Godfrey and S. J. Williams, Chem. Sci., 2020, Accepted Manuscript , DOI: 10.1039/C9SC05248H

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