Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy.
Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand alpha-galactosylceramide (alpha-GalCer) or the sphingosine-truncated alpha-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and gamma interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli. The adjuvant activity of alpha-GalCer enhances both priming and boosting of CD8(+) T cells to coadministered peptide or protein antigens, including a peptide encoding the clinically relevant, HLA-A2-restricted epitope of the human tumor antigen NY-ESO-1. Importantly, alpha-GalCer was used to induce CD8(+) T cells to antigens delivered orally, despite the fact that this route of administration is normally associated with blunted responses. Only T cell responses induced in the presence of iNKT cell stimulation, whether by the i.v. or oral route, were capable of eradicating established tumors. Together these data highlight the therapeutic potential of iNKT cell ligands in vaccination strategies, particularly "heterologous prime-boost" strategies against tumors, and provide evidence that iNKT cell stimulation may be exploited in the development of oral vaccines.
Silk
Jonathan D
JD
Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Hermans
Ian F
IF
Gileadi
Uzi
U
Chong
Tsung Wen
TW
Shepherd
Dawn
D
Salio
Mariolina
M
Mathew
Bini
B
Schmidt
Richard R
RR
Lunt
Sarah Jane
SJ
Williams
Kaye J
KJ
Stratford
Ian J
IJ
Harris
Adrian L
AL
Cerundolo
Vincenzo
V
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000737:chemistry* / Q000276:immunology*; D055610:Antigens, CD1d; D051940:B7-2 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002469:Cell Separation; D003470:Culture Media / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D051193:Toll-Like Receptors
D015703:Antigens, CD; D018949:Antigens, CD1; D055610:Antigens, CD1d; D051940:B7-2 Antigen; C526877:CD1D protein, human; C497965:Cd86 protein, mouse; D003470:Culture Media; D000939:Epitopes; D015789:HLA-A2 Antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors