title: Activation of human invariant natural killer T cells with a thioglycoside analogue of α-galactosylceramide.
abstract: Activation of CD1d-restricted invariant NKT (iNKT) cells with the glycolipid α-galactosylceramide (α-GalCer) confers protection against disease in murine models, however, clinical trials in humans have had limited impact. We synthesized a novel thioglycoside analogue of α-GalCer, denoted α-S-GalCer, and tested its efficacy for stimulating human iNKT cells in vitro. α-S-GalCer stimulated cytokine release by iNKT cells in a CD1d-dependent manner and primed CD1d(+) target cells for lysis. α-S-GalCer-stimulated iNKT cells induced maturation of monocyte-derived dendritic cells into antigen-presenting cells that released IL-12 and small amounts of IL-10. The nature and potency of α-S-GalCer and α-GalCer in human iNKT cell activation were similar. However, in contrast to α-GalCer, α-S-GalCer did not activate murine iNKT cells in vivo. Because of its enhanced stability in biological systems, α-S-GalCer may be superior to α-GalCer as a parent compound for developing adjuvant therapies for humans.
authors.affiliation: Institute of Molecular Medicine, Trinity College Dublin, St James's Hospital, Dublin, Ireland.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Hogan
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Reilly
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Dunne
authors.forename: Ravindra T
authors.initials: RT
authors.lastname: Dere
authors.forename: Shijuan G
authors.initials: SG
authors.lastname: Zeng
authors.forename: Cashel
authors.initials: C
authors.lastname: O'Brien
authors.forename: Sylvie
authors.initials: S
authors.lastname: Amu
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Mark A
authors.initials: MA
authors.lastname: Exley
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.forename: Xiangming
authors.initials: X
authors.lastname: Zhu
authors.forename: Derek G
authors.initials: DG
authors.lastname: Doherty
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013862:Thiogalactosides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D013865:Thioglycosides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology
chemical_list: D055610:Antigens, CD1d; D005699:Galactosylceramides; D013862:Thiogalactosides; D013865:Thioglycosides; C561494:alpha-S-galactosylceramide; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma