Amide analogues of CD1d agonists modulate iNKT-cell-mediated cytokine production.
Invariant natural killer T (iNKT) cells are restricted by the non-polymorphic MHC class I-like protein, CD1d, and activated following presentation of lipid antigens bound to CD1d molecules. The prototypical iNKT cell agonist is α-galactosyl ceramide (α-GalCer). CD1d-mediated activation of iNKT cells by this molecule results in the rapid secretion of a range of pro-inflammatory (Th1) and regulatory (Th2) cytokines. Polarization of the cytokine response can be achieved by modifying the structure of the glycolipid, which opens up the possibility of using CD1d agonists as therapeutic agents for a range of diseases. Analysis of crystal structures of the T-cell receptor-α-GalCer-CD1d complex led us to postulate that amide isosteres of known CD1d agonists should modulate the cytokine response profile upon iNKT-cell activation. To this end, we describe the synthesis and biological activity of amide analogues of α-GalCer and its non-glycosidic analogue threitol ceramide (ThrCer). All of the analogues were found to stimulate murine and human iNKT cells by CD1d-mediated presentation to varying degrees; however, the thioamide and carbamate analogues of ThrCer were of particular interest in that they elicited a strongly polarized cytokine response (more interferon-gamma (IFN-γ), no interleukin-4 (IL-4)) in mice. While the ThrCer-carbamate analogue was shown to transactivate natural killer (NK) cells, a mechanism that has been used to account for the preferential production of IFN-γ by other CD1d agonists, this pathway does not account for the polarized cytokine response observed for the thioamide analogue.
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
Justyna
J
Wojno
John-Paul
JP
Jukes
Hemza
H
Ghadbane
Dawn
D
Shepherd
Gurdyal S
GS
Besra
Vincenzo
V
Cerundolo
Liam R
LR
Cox
D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry / Q000276:immunology*; D002642:Chick Embryo; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000276:immunology*; D005699:Galactosylceramides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology*; D013402:Sugar Alcohols / Q000737:chemistry / Q000494:pharmacology
D055610:Antigens, CD1d; D016207:Cytokines; D005699:Galactosylceramides; D013402:Sugar Alcohols; C493154:alpha-galactosylceramide; C003460:threitol