Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell–mediated immunotherapy
Jonathan D. Silk, … , Adrian L. Harris, Vincenzo Cerundolo
Jonathan D. Silk, … , Adrian L. Harris, Vincenzo Cerundolo
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1800-1811. https://doi.org/10.1172/JCI22046.
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Article Immunology

Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell–mediated immunotherapy

Abstract

Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand α-galactosylceramide (α-GalCer) or the sphingosine-truncated α-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and γ 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 α-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, α-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.

Authors

Jonathan D. Silk, Ian F. Hermans, Uzi Gileadi, Tsung Wen Chong, Dawn Shepherd, Mariolina Salio, Bini Mathew, Richard R. Schmidt, Sarah Jane Lunt, Kaye J. Williams, Ian J. Stratford, Adrian L. Harris, Vincenzo Cerundolo

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Oral administration of soluble antigen and α-GalCer induces functional T...
Oral administration of soluble antigen and α-GalCer induces functional T cell responses with potent restimulatory capacity. (A) Whole OVA was administered by gavage to C57BL/6 or CD1d–/– mice as in Figure 6. Induction of OVA257–264 CD8+ T cell responses was assessed in the blood 7 days later (FACS profiles and top graph) and 7 days after subsequent restimulation by s.c. injection with OVA protein in CFA (lower graph). (B) OVA257-264–specific T cell responses were induced in C57BL/6 mice by oral administration of OVA as in Figure 6 (top panel) and were subsequently restimulated by i.v. injection with vacc-OVA 9 days later (lower panel). Responses induced 7 days after restimulation are presented together with those observed in control animals that received vaccinia alone and those of a naive group.