A role for macrophage IκB kinase in the mucosal adjuvant activity of edema toxin for sublingual vaccines (46.2)

Abstract

Abstract It has been demonstrated that nuclear factor κB (NF-κB) activation by IκB kinase (Ikk)β deletion in macrophages increases pro-inflammatory cytokines responses and enhances pathogen clearance. To address whether this pathway also regulates the mucosal adjuvant activity of edema toxin (EdTx), LysMcre x Ikkβf/f (IkkβΔMø) mice with Ikkβ-deleted macrophages were sublingually immunized with 50µg of Yersinia pestis F1V fusion protein with or without 15µg of EdTx as an adjuvant. Both control and IkkβΔMø mice immunized with F1V+EdTx developed higher levels of serum Abs, i.e., IgG, IgG1, IgG2a and IgA, when compared to mice immunized with F1V alone. The IkkβΔMø mice exhibited higher serum IgG2a levels (and IgG2a:IgG1 ratio) than control counterpart immunized with F1V+EdTx, suggesting that immune responses to F1V are biased toward Th1-type. These mice also showed elevated levels of F1V-specific serum IgA Abs than control littermates. The effect of Ikkβ deletion was more pronounced in secretory Abs since EdTx as adjuvant promoted higher fecal IgA Abs, as well as IgG and IgA Ab titers in saliva and vaginal washes of IkkβΔMø mice. These studies reveal a new role for macrophages and NF-κB in shaping mucosal immune responses induced by EdTx derivative adjuvants via the sublingual mucosa.