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Mucosal Immune Responses Associated with NKT Cell Activation and Dendritic Cell Expansion by Nasal administration of α-galactosylceramide in the Nasopharynx

Shingo Umemoto,Satoru Kodama*,Takashi Hirano,Kenji Noda,Masashi Suzuki

Objective: Intranasal immunization is an effective method to induce mucosal immune responses in the upper respiratory tract.α-galactosylceramide (α-GalCer) is considered as one of the most potent candidates for a mucosal adjuvant. In the present study, mucosal immune responses in the nasopharynx associated with NKT cell activation by nasal administration of α-GalCer were examined for inducing protective immunity in the nasopharynx, with the ultimate goal of developing a mucosal vaccine for preventing upper respiratory infectious diseases. Methods: Mice were administered α-GalCer intranasally as a ligand for NKT cells, without any antigen, weekly total three times. One week after the final administration of α-GalCer, mice were killed, and nasal immune responses were examined. Dendritic cells (DCs) in nasal-associated lymphoid tissue (NALT), a mucosal inductive site, were examined by immunohistochemistry. DCs, NKT cells, and B cells in NALT and nasal passage (NP) were examined by flow cytometry. Cytokine-producing CD4+ T cells were also examined by flow cytometry. Quantification of immunoglobulin (Ig)-producing cells was examined by enzyme-linked immunospot (ELISPOT) assay. In addition, bacterial challenges with live Haemophilus influenzae (Hi) and Streptococcus pneumoniae (Sp) were performed, and bacterial clearance from nasopharynx was examined. Results: After nasal immunization of α -GalCer, DCs increased in NALT. Antibody-producing cells, mainly those that produce IgA, significantly increased in the NP, a mucosal effector site. Interleukin (IL)-17-producing Th 17 cells were also induced in the NP. Bacterial challenges with live Hi and Sp resulted in enhanced clearances of both bacterial species from the nasopharynx. It is interesting that bacterial clearance was impaired by IL-17 neutralization. Conclusion: Nasal vaccination is effective for the induction of protective immunity against upper respiratory infection. The results of the present study demonstrated that nasal administration of α-GalCer could activate NKT cells in the nasopharynx, followed by the maturation of DCs, B cells, and some cytokine-producing CD4+ T cells. These findings suggest that the activation of NKT cells by nasal administration of α-GalCer induced protective immunity in the nasopharynx, possibly involving the interaction with DCs and induction of Th17 cells.