Invariant NKT (iNKT) cells represent a unique subset of T lymphocytes that have an important regulatory role in the protection against tumour cells, auto-immune diseases and certain infections. iNKT cells recognize the prototypical ligand α-galactosylceramide (α-GalCer), presented by CD1d.
This presentation will focus on our attempts to design α-GalCer analogues that polarize the cytokine response towards Th1, which is desirable for defense against tumors and various intracellular pathogens. Towards this end we carefully investigated modifications at the sugar part of α-GalCer.
We will demonstrate the ability of analogues modified at the 6’’-position of the galactose ring to induce a polarized Th1 response. Crystallographic studies indicated that two lead compounds, i.e. NU-a-GalCer (1) and PyrC-a-GalCer (2), undergo additional interactions with either CD1d or the T-cell receptor (TCR) of iNKT cells. Both cases illustrate a unifying concept that judiciously chosen modifications of α-GalCer’s carbohydrate moiety may enhance the stability of the CD1d-glycolipid-TCR complex and lead to a more robust induction of Th1 cytokines in mice, while retaining activity in human iNKT cells.