title: Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung.
abstract: 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.
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Department of Immunology, Houston, Texas 77054, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Courtney
authors.forename: Prakash
authors.initials: P
authors.lastname: Thapa
authors.forename: Shailbala
authors.initials: S
authors.lastname: Singh
authors.forename: Ameerah M
authors.initials: AM
authors.lastname: Wishahy
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.forename: Jagannadha
authors.initials: J
authors.lastname: Sastry
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000008:administration & dosage* / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects / Q000276:immunology; D007275:Injections, Intravenous; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D005699:Galactosylceramides