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Unmethylated CpG oligodeoxynucleotides (ODNs), by activating cells of the innate immune system, such as dendritic cells and NK cells, are potent adjuvants for type 1 immune responses. In the present study, we aimed to investigate the role of invariant NKT (iNKT) cells, a subset of lipid-reactive innate lymphocytes, in CpG ODN-induced innate and acquired type 1 responses. Our data show that, in response to the CpG ODN type B 1826, splenic and hepatic iNKT cells become activated and produce IFN-gamma, but not IL-4, both in vitro and in vivo. This Th1 bias is independent from the Ag-presenting molecule CD1d and strongly requires IL-12, at least in vitro. We also report that iNKT cell activation, in response to CpG ODN type B, results in the transactivation of NK cells. To address the potential role of iNKT cells in type 1 innate immunity induced by CpG ODN, a murine model of malignant melanoma was used. We show that CpG ODN type B protects mice against B16F10-induced lung metastasis in wild-type mice, but in a less efficient manner in iNKT cell-deficient animals. Finally, we report that immunization of wild-type mice with CpG ODN type B plus keyhole limpet hemocyanin biases the immune response toward a Th1 direction, an effect strongly mediated by iNKT cells. We conclude that iNKT cells amplify the innate and acquired response to CpG ODN type B, with potentially important consequences for the regulation of immune responses.

The development of safe and potent mucosal adjuvants remains a major objective in vaccinology. The potential usefulness of filamentous haemagglutinin (FHA) of Bordetella pertussis as an adjuvant was assessed in a mouse model. The glutathione-S-transferase of Schistosoma mansoni (Sm28GST) was used for intranasal administration, while the gut-resistant keyhole limpet haemocyanin (KLH) was administrated by the oral route. For both antigens, coadministration with FHA increased antigen-specific immunoglobulin titres. This adjuvant effect did not require chemical cross-linking or direct interaction between FHA and the antigen tested. FHA also behaved as an adjuvant by the subcutaneous route, indicating that its adjuvanticity is not restricted to binding to mucosal surfaces. The FHA-induced adjuvanticity was also observed in mice with high anti-FHA antibody titres as a result of antipertussis vaccination, indicating that pre-existing anti-FHA antibodies do not impair FHA adjuvanticity. No mRNA coding for proinflammatory cytokines was induced in the lungs after intranasal FHA administration. However, an increase in the levels of mRNAs coding for B7-1, transforming growth factor (TGF)-beta and major histocompatibility complex (MHC)-II was detected in the lungs after FHA administration. Although the molecular mechanisms of the FHA-induced adjuvanticity remain to be elucidated, the data presented here indicate that this adhesin, already assessed for human use as a pertussis vaccine constituent, represents a promising adjuvant to improve the humoral immune response when given by mucosal routes.

A common property of allergens is their potential to generate type 2 cytokine responses. To understand the mechanisms involved in this phenomenon, we have evaluated the polarizing potential of a major allergen, Dermatophagoides pteronyssinus 1 (Der p 1), in an heterologous immunization system using the glutathione S-transferase of the parasite Schistosoma mansoni (Sm28-GST) as immunogen. In previous studies, we showed that immunization with the Sm28-GST emulsified in CFA induced a nonpolarized immune response. In contrast, when alum was used as adjuvant, a type 2 immune response was induced against Sm28-GST. Using this experimental model, we examined whether the administration of Der p 1 together with Sm28-GST influenced the nonpolarized and/or the Th2 profiles induced by the CFA or the alum immunization, respectively. Our results showed that the introduction of Der p 1 in the CFA immunization protocol was associated with diminished anti-Sm28-GST IgG2a Ab titers, reduced IFN-gamma mRNA expression, and frequency of IFN-gamma-producing cells. In contrast, the introduction of Der p 1 in the alum protocol did not affect IL-4 or Ig isotype responses. The effect of Der p 1 was specific, since coimmunization with tetanus toxin fragment C did not affect the profile of the response against Sm28-GST. Furthermore, inactivation of Der p 1 reduced its ability to modify the immune response profile, suggesting that its protease activity played an important role in deviating the immune response. Our results suggest that the Der p 1 has the ability to modify the profile of an immune response by modulating the balance between the polarizing cytokines IL-4 and IFN-gamma.