Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell–mediated immunotherapy
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
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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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 C...
Oral administration of soluble antigen and α-GalCer induces functional CTLs. (A) Whole OVA was administered by gavage (30 mg/mouse) together with either α-GalCer (8 μg/mouse) or vehicle. Induction of OVA257–264 CD8+ T cell responses was assessed in the blood 7 days later. (B) Cytolytic activity of the induced OVA257–264–specific response was assessed in vivo 11 days after OVA administration against syngeneic splenocytes loaded with titrated doses of OVA257–264 peptide as indicated in right-hand diagram. Different CFSE concentrations were used to distinguish between the various peptide-loaded populations, while a control population without peptide was labeled with chloromethyl-benzoyl-aminotetramethyl-rhodamine (CMTMR) alone. Representative FACS profiles for each treatment group are shown. Antigen-specific lysis was calculated at 16 hours after target cell administration, with percent specific lysis calculated as the mean proportion of antigen-loaded cells lysed relative to that of control populations without antigen. (C) Growth of s.c. implanted E.G7-OVA tumors was assessed in animals treated therapeutically with a combination of OVA protein and α-GalCer, by the i.v. or oral route, or with oral OVA and vehicle, 5 days after tumor challenge.