Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung

University of Texas M.D. Anderson Cancer Center, Department of Immunology, Houston, Texas 77054, USA.
European Journal of Immunology (Impact Factor: 4.03). 11/2011; 41(11):3312-22. DOI: 10.1002/eji.201041359
Source: PubMed


Efficient induction of antigen-specific immunity is achieved by delivering multiple doses of vaccine formulated with appropriate adjuvants that can harness the benefits of innate immune mediators. The synthetic glycolipid α-galactosylceramide (α-GalCer) is a potent activator of NKT cells, a major innate immune mediator cell type effective in inducing maturation of DCs for efficient presentation of co-administered antigens. However, systemic administration of α-GalCer results in NKT cell anergy in which the cells are unresponsive to subsequent doses of α-GalCer. We show here that α-GalCer delivered as an adjuvant by the intranasal route, as opposed to the intravenous route, enables repeated activation of NKT cells and DCs, resulting in efficient induction of cellular immune responses to co-administered antigens. We show evidence that after intranasal delivery,α-GalCer is selectively presented by DCs for the activation of NKT cells, not B cells. Furthermore, higher levels of PD-1 expression, a potential marker for functional exhaustion of the NKT cells when α-GalCer is delivered by the intravenous route, are not observed after intranasal delivery. These results support a mucosal route of delivery for the utility of α-GalCer as an adjuvant for vaccines, which often requires repeated dosing to achieve durable protective immunity.

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Available from: Dapeng Zhou, Dec 18, 2014
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    • "Antigen-specific responses of CD4 + and CD8 + T lymphocytes isolated from cervical lymph nodes, lungs, and spleens of the immunized animals at different times post immunization were determined by IFN-␥ ELISpot assay as described previously [21] [22]. "
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    • "Single cell suspensions isolated from the lungs, cervical lymph nodes and spleen of immunized mice were analyzed for activation and proliferation of NKT cells. Cells were stained with Aqua Live/Dead reagent (Invitrogen, Carlsbad, CA), Pacific Blue-conjugated CD3 (clone 500A2, BD Biosciences, San Jose, CA) and the APC-conjugated mouse CD1d tetramer loaded with PBS57 (provided by NIH tetramer facility at Emory University, Atlanta, GA) by the procedure described previously [26]. The activation status of NKT cells isolated from animals at different time points after immunization was determined by intra-cellular staining for IFN-γ production. "
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    • "This may be in part due to the fact that 7DW8-5 was administered IM in this study, while all the data with α-GalCer was obtained after IV administration. In fact, intranasal or intradermal delivery of α-GalCer has been shown to reduce iNKT cell anergy compared with IV administration in mice [56,57]. "
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