Pertussis Toxin Enhances Th1 Responses by Stimulation of Dendritic Cells

Abstract

Pertussis toxin (PTX) has been widely used as an adjuvant to induce Th1-mediated organ-specific autoimmune diseases in animal models. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that dendritic cells (DC) stimulated with PTX (PTX-DC) were able to substitute for PTX to promote experimental autoimmune uveitis (EAU). EAU induced by PTX-DC revealed a typical Th1 response, characterized by high uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP)-specific IFN-γ and IL-12 production in the draining lymph nodes, as well as increased levels of anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum of IRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells to produce the Th1 cytokine, IFN-γ. After being stimulated with PTX, DC exhibited up-regulation of MHC class II, CD80, CD86, CD40, and DEC205. PTX-DC had also increased allostimulatory capacity and IL-12 and TNF-α production. Serum IL-12 was increased in naive mice that received PTX-DC i.p. In addition, PTX activated extracellular signal-regulated kinase in DC. Following the inhibition of extracellular signal-regulated kinase signaling, the maturation of PTX-DC was reduced. Subsequently, the ability of PTX-DC to promote IFN-γ production by T cells in vitro and to induce EAU in vivo was blocked. The results suggest that PTX might exert an adjuvant effect on DC to promote their maturation and the production of proinflammatory cytokines, thereby eliciting a Th1 response.

Experimental Autoimmune Encephalomyelitis (EAE) Induced by Antigen Pulsed Dendritic Cells in the C57BL/6 Mouse: Influence of Injection Route

“…Stimulation of DCs with pertussis toxin exhibited upregulation of MHC class II, CD80, CD86, CD40 and increased their allostimulatory capacity and IL-12 and TNF-a production [19]. Regarding our results pertussis toxin might also exert an adjuvant effect on DCs promoting their capacity to induce EAE in mice.…”

“…Pertussis toxin is an exotoxin produced by Bordetella pertussis, which is reported to have adjuvant properties with Th1 induction effects [19]. This toxin has been widely used to enhance the signs of EAE [25,41].…”

Strategies to alleviate original antigenic sin responses to influenza viruses

“…The administration of adjuvants may shift Ag presentation from memory B cells to DCs and enhance cellular immune response. Both PT and CpG promote maturation of DCs, induce them to produce cytokines including IL-12 and IFN-γ, and enhance Ag presentation (14,17,19,32). The mechanism by which NE enhances immunogenicity is not completely understood, but available data suggest that MF59 triggers a local inflammatory environment by engaging muscle cells at the injection site, which then indirectly activates DCs (20).…”

“…Of these bacterial products, killed Bordetella pertussis is a potent adjuvant (11), and its components including B. pertussis toxin (PT) and B. pertussis endotoxin (LPS) have been shown to block or reverse carrier-mediated hapten suppression (12,13). Specifically, PT stimulates DCs to up-regulate MHC class II and costimulatory molecules [cluster of differentiation (CD)80, CD86, CD40, and dendritic and epithelial cell (DEC)205] to produce IL-12 and TNF-α and to up-regulate phosphorylation of ERK (14). This overall DC activation by PT elicits a Th1 response by promoting T cells to produce IFN-γ.…”

Pertussis toxin as an adjuvant suppresses the number and function of CD4+CD25+ T regulatory cells

“…Recent work has shown that PTx actually increases adhesion molecule expression that initiates leukocyte infiltration into the brain [16]. Further, PTx appears to induce the maturation of dendritic cells [17][18][19][20][21], which results in the expansion of T effector cells and secretion of IFN-c [22].…”