Mast Cells Contribute to the Mucosal Adjuvant Effect of CTA1–DD after IgG-Complex Formation

Abstract

Mast cell activation is one of the most dramatic immune-mediated responses the body can encounter. In the worst scenario (i.e., anaphylaxis), this response is fatal. However, the importance of mast cells as initiators and effectors of both innate and adaptive immunity in healthy individuals has recently been appreciated. It was reported that mast cell activation can be used as an adjuvant to promote Ag-specific humoral immune responses upon vaccination. In this study, we have used a clinically relevant mucosal adjuvant, cholera toxin A1 subunit (CTA1)–DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A. CTA1–DD in combination with polyclonal IgG induced degranulation and production of TNF-α from mouse mast cells. Furthermore, CTA1–DD and polyclonal IgG complex induced mast cell degranulation in mouse skin tissue and nasal mucosa. We also found that intranasal immunization with hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin admixed with CTA1–DD complexed with polyclonal IgG greatly enhanced serum IgG anti-NP Ab responses and stimulated higher numbers of NP-specific plasma cells in the bone marrow as compared with that observed in mice immunized with NP-chicken gammaglobulin with CTA1–DD alone. This CTA1–DD/IgG complex-mediated enhancement was mast cell dependent because it was absent in mast cell-deficient KitW-sh/W-sh mice. In conclusion, our data suggest that a clinically relevant adjuvant, CTA1–DD, exerts additional augmenting effects through activation of mucosal mast cells, clearly demonstrating that mast cells could be further exploited for improving the efficacy of mucosal vaccines.

Maximal Adjuvant Activity of Nasally Delivered IL-1α Requires Adjuvant-Responsive CD11c+ Cells and Does Not Correlate with Adjuvant-Induced In Vivo Cytokine Production

“…In the previous studies, nasal lavage IL-6 production was slightly increased in WT→KO mice given 0.25 or 4 μg IL-1α nasally and hematopoietic cell expression of IL-1R1 correlated with maximal adjuvant activity. Additionally, mast cells have been reported to be required for the maximal adjuvant activities of imiquimod[35] and CTA1-DD/IgG[34]. Therefore, we chose to evaluate the requirement for mast cells in the nasal adjuvant activity of IL-1α.…”

“…However, other studies have evaluated the roles of individual cell types in the response to adjuvant delivery using mouse strains with targeted mutations. While an absolute requirement has been demonstrated for mast cells in the adjuvant activity of imiquimod and CTA1-DD/IgG(intranasal and transcutaneous immunization, respectively) [34, 35], a previous study by Hou et al demonstrated that the adjuvant activity of systemically delivered CpG required adjuvant-responsive CD11c + cells for maximal adjuvant activity [36]. Elucidating the requirement for an adjuvant-responsive mucosal barrier following vaccination with one potent mucosal vaccine adjuvant, IL-1α, may provide insight into the role of the mucosal barrier and help identify cell types important in the generation of adaptive immune responses to mucosally delivered vaccines.…”

Antigen/IgG immune complex‐primed mucosal mast cells mediate antigen‐specific activation of co‐cultured T cells

“…Recently the roles of mast cells have been extended to providing adjuvanticity for vaccination. [2][3][4][32][33][34] We have come to recognize that greater levels of antigen-specific immune responses could be obtained when the mucosal adjuvant CTA1-DD, by virtue of its unspecific binding to immunoglobulins, was complexed with IgG forming immune complexes that could activate nasal CTMC. 4 In contrast, MMC failed to be activated by CTA1-DD/IgG immune complexes.…”

“…More recently, mast cells have also been depicted in their potential to boost mucosal vaccination as mast cell activators are demonstrated to be powerful mucosal adjuvants . We have previously shown robust adjuvanticity exerted by Fc γ receptor‐mediated mast cell activation …”

“…2 We have previously shown robust adjuvanticity exerted by Fcc receptor-mediated mast cell activation. 3,4 Mast cells represent a heterogeneous family of bone marrow (BM) -derived tissue resident cells. There are two phenotypically distinct rodent mast cell phenotypes, namely connective tissue mast cells (CTMC) and mucosal mast cells (MMC), which are classified depending on tissue distribution, histochemical staining and mediator composition.…”