Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

Abstract

Pertussis toxin (PTX) has potent immunologic adjuvant activity in vivo and concomitantly enhances both T helper type (Th) 1 and Th2 cytokine responses. The PTX-induced enhancement of Th1 and Th2 immunity is mediated via the activation of antigen presenting cells (APCs), but the underlying mechanism is not known.Here we asked whether the adjuvant activity of PTX on T cell immunity was mediated by cytokines and/or costimulatory signals.The results show that in vivo blockade of CD28-CD80/86 costimulation essentially abrogated PTXmediated enhancement of antigen-specific Th1 and Th2 responses. Blockade of CD40L-CD40 interactions was less efficient in inhibiting PTX-mediated enhancement of Th1 and Th2 responses. In contrast, the adjuvant activity of PTX was not mediated via cytokines, because neither Th1 nor Th2 responses were substantially impaired in mice deficient for IL-12, IFN-γ, IL-4, IL-5, or IL-6.Collectively, the data suggest that PTX mediates its adjuvant effects on T cell cytokine differentiation and clonal expansion via the modulation of costimulatory molecules on APCs. Understanding the costimulatory pathways targeted by PTX could lead to the design of novel adjuvants that selectively induce Th1 or Th2 immunity.

Induction of polyclonal CD8+ T cell activation and effector function by Pertussis toxin

“…The upregulation of CD28 on CD8+ T cells by PTX suggested that the CD80/86 pathway could play a role, similar to previous observations with CD4+ T cells [16]. …”

“…Several studies showed that it activates APCs and upregulates CD80, CD86, and MHC class II molecules, suggesting that its effects on T cells are mediated indirectly [14]. Along these lines, Wakatsuki and colleagues provided evidence that PTX bound to APCs was critical for its T cell activating properties, and Denkinger and colleagues showed that PTX-induced clonal expansion and cytokine differentiation of Th1 and Th2 cells was primarily dependent on costimulation via CD80/86 molecules [15;16]. However, some studies have suggested a direct effect of PTX on T cells [17;18], and it is conceivable that modulation of CD28 and/or CTLA-4 expression on T cells could contribute to the PTX adjuvant activity.…”

Anaphylaxis and Mortality Induced by Treatment of Mice with Anti–VLA-4 Antibody and Pertussis Toxin

“…vascular endothelial cells) resulting in the subsequent activation of CD4 + T cells and death of the animals. This view is consistent with studies showing a direct effect of PTX on APCs leading to the upregulation of costimulatory molecules and enhanced cytokine production (35,36,40). …”

A Single Nucleotide Polymorphism inTyk2Controls Susceptibility to Experimental Allergic Encephalomyelitis

“…PTX also enhances the ability of the APC to activate T cells by inducing dendritic cell maturation (62) and up-regulating expression of the co-stimulatory molecules CD80 and CD86 in the spleen and spinal cord (40, 41, 63). PTX-induced cytokine production and T cell clonal expansion are thought to occur primarily through the CD28:CD80/86 costimulatory pathway (64). The PTX-induced changes in EAE susceptibility of B10.D1 mice cannot be attributed solely to effects on either T cells or APCs based on these experiments.…”