Non-glycosidic compounds can stimulate both human and mouse iNKT cells.

John‐Paul Jukes,Liam R Cox,Uzi Gileadi,Ting‐Fong Yu,Vincenzo Cerundolo,Dawn Shepherd,Hemza Ghadbane,Gurdyal S Besra

doi:10.1002/eji.201546114

John‐Paul Jukes, Liam R Cox + Show 6 more

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https://doi.org/10.1002/eji.201546114

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Abstract

Invariant natural killer T (iNKT) cells recognize CD1d/glycolipid complexes and upon activation with synthetic agonists display immunostimulatory properties. We have previously described that the non‐glycosidic CD1d‐binding lipid, threitolceramide (ThrCer) activates murine and human iNKT cells. Here, we show that incorporating the headgroup of ThrCer into a conformationally more restricted 6‐ or 7‐membered ring results in significantly more potent non‐glycosidic analogs. In particular, ThrCer 6 was found to promote strong anti‐tumor responses and to induce a more prolonged stimulation of iNKT cells than does the canonical α‐galactosylceramide (α‐GalCer), achieving an enhanced T‐cell response at lower concentrations compared with α‐GalCer both in vitro, using human iNKT‐cell lines and in vivo, using C57BL/6 mice. Collectively, these studies describe novel non‐glycosidic ThrCer‐based analogs that have improved potency in iNKT‐cell activation compared with that of α‐GalCer, and are clinically relevant iNKT‐cell agonists.

Highlights

Invariant natural killer T cells are a specialized subset of T cells that recognize glycolipids presented in the context of the non-polymorphic MHC-class I like molecule, CD1d
In order to extend the analysis of the ability of ThrCer analogs to activate Invariant natural killer T (iNKT)-cells in vivo, we assessed their ability to promote a response in a murine model
We performed binding assays using in vitro-loaded murine recombinant CD1d molecules and in vitro-refolded murine Vα14/Vβ8 iNKT-cell TCR

Summary

Introduction

Invariant natural killer T (iNKT) cells are a specialized subset of T cells that recognize glycolipids presented in the context of the non-polymorphic MHC-class I like molecule, CD1d. INKT cells have been shown to promote immunity through their capacity to suppress myeloid-derived suppressor cells [28, 29]. Since these properties are a prerequisite for successful vaccine adjuvants, iNKT-cell agonists have emerged as ∗.

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