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Non‐glycosidic compounds can stimulate both human and mouse i NKT cells
Author(s) -
Jukes JohnPaul,
Gileadi Uzi,
Ghadbane Hemza,
Yu TingFong,
Shepherd Dawn,
Cox Liam R.,
Besra Gurdyal S.,
Cerundolo Vincenzo
Publication year - 2016
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201546114
Subject(s) - cd1d , glycosidic bond , glycolipid , biology , natural killer t cell , in vitro , t cell receptor , in vivo , stimulation , microbiology and biotechnology , t cell , biochemistry , immunology , immune system , cytotoxic t cell , endocrinology , enzyme , genetics
Invariant natural killer T ( i NKT) 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 i NKT 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 i NKT 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 i NKT‐cell activation compared with that of α‐GalCer, and are clinically relevant i NKT‐cell agonists.