Harnessing NKT cells in cancer vaccination strategies


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Vincenzo Cerundolo

University of Oxford, UK

Abstract

Harnessing NKT cells in cancer vaccination strategies

We have previously demonstrated that activation of invariant NKT (iNKT) cells results in DC maturation and assists priming of antigen specific T lymphocytes. We have recently extended these results by assessing priming of B lymphocytes and characterizing the parameters controlling the activation of iNKT cells and binding affinity of iNKT cell T Cell Receptor (TCR) to CD1d/lipid complexes. The crystal structure of human CD1d-alpha-Galactosyl Ceramide (alpha -GalCer) demonstrated that alpha -GalCer exploits fully the binding capacity of CD1d. Using planar lipid bilayers and surface plasmon resonance, we found that shortening of the sphingosine chain of alpha -GalCer reduces the iNKT cell TCR affinity by 100 fold, resulting in changes to the iNKT cell immunological synapse, polarization of iNKT cell cytotoxic granules and iNKT cell activation. In contrast, variations in either the length or saturation of the acyl chain do not alter iNKT cell TCR affinity. Analysis of previously reported structures of empty and loaded human CD1d molecules suggests that incomplete occupation of the binding groove by a shortened sphingosine chain could result in conformational differences at the TCR recognition surface. This indirect effect provides a general mechanism by which the length of the lipid chain occupying the CD1d C’ channel plays a role in controlling the affinity of lipid specific CD1d restricted T cells. Analysis of iNKT cell dependent DC maturation and T cell priming mediated by a panel of iNKT cell agonists with different TCR affinities will be discussed.