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

Abstract

Pertussis toxin (PTX) has pronounced adjuvant activity and strongly enhances innate and adaptive immune responses, including increased antibody production and Th1/Th2 cytokine production. Adjuvant effects of PTX on Th1 and Th2 cells are primarily mediated via CD80/86 costimulation via enhanced expression of these molecules by APCs. However, it has remained unresolved whether PTX modulates the expression of costimulatory and inhibitory molecules on CD4+ and CD8+ T cells. To address this question, we determined the expression kinetics of CD28, CTLA-4, and CD40L on spleen CD4+ and CD8+ T cells after incubation with PTX. The results show that PTX upregulated the expression of CD28 by CD8+ T cells, but not by CD4+ T cells. In contrast, the expression of CTLA-4 and CD40L was not substantially altered on CD4+ or CD8+ T cells. CD28 upregulation by CD8+ T cells was paralleled by upregulation of CD69 and the induction of IFN-γ, Granzyme B (GrB), and IL-17. CD8+ T cell activation and cytokine production could be substantially blocked with anti-CD80 and CD86 antibodies, consistent with CD28 mediated signaling. Treatment of highly purified CD8+ T cells with PTX resulted in upregulation of CD28 and CD69, and production of IFN-γ. Incubation with CD28 mAb further enhanced this effect, suggesting that PTX has direct effects on CD8+ T cells which are enhanced by CD80/86-mediated costimulation provided by APCs.

Histamine H2receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis

“…The cytokine hyperresponsiveness in Gα i2 ‐knockout mice was subsequently shown to be due to abnormal T‐cell receptor signaling (72). Although this finding suggests a direct role for PTX in regulating T‐cell effector responses and some studies have suggested a direct effect of PTX on T cells (73), including increased expression of CD28 paralleled by up‐regulation of CD69 and induction of IFN‐γ, granzyme B, and IL‐17 (74), the preponderance of the data suggests that PTX acts indirectly on T cells by activating APCs and up‐regulating CD80, CD86, and major histocompatibility complex class II expression (58–63).…”

Bordetella protein toxins

“…In addition to its action on CD4 + T cells, PTX induces the activation of CD8 + T cells [97]. PTX strongly upregulates the expression of CD28 by CD8 + T cells, but not by CD4 + T cells, as well as the expression of CD69, IFN-γ, IL-17, and granzyme B by purified CD8 + T cells in a CD80-and CD86-dependent manner.…”

Desenvolvimento de vacinas proteicas contra Streptococcus pneumoniae: caracterização dos componetes adjuvantes da vacina celular pertussis e análise de novas combinações vacinais.

“…É possível que a PT apresente um mecanismo semelhante ao das toxinas colérica (CT -produzida por Vibrio cholerae) e termo-lábel (LT -produzida por E. coli), que também são exotoxinas heterohexamericas do tipo AB 5 . Estas toxinas, CT e LT, além de ter uma ação toxica semelhante ao da PT, também atuam como um imunógeno e adjuvante de mucosa induzindo IgG e IgA contra antígenos co-administrados por via nasal, oral ou parental (Holmgren, Adamsson, 2005 e CD69 e na expressão de IFN-γ, granzima B e IL-17 (Murphey, Chang et al, 2011). In vitro foi demonstrado que a PT é capaz de estimular a expressão das moléculas coestimulatorias CD40, CD83e CD86 e do MHC classe II em células dendríticas (Wang, Yang, 2006 Assim, em nosso modelo, a atividade enzimática de PT também parece não ser essencial para a ação adjuvante.…”

“…Além disso a PT foi capaz de aumentar a expressão de moléculas co-estimulatórias na superfície de células B, macrófagos e linfócitos T (Ryan, McCarthy, 1998). Estudos mais recentes mostram que a ação adjuvante de PT envolve estimulação e maturação de células apresentadoras de antígenos (APC) e ativação de linfócitos T CD8 + (Murphey, Chang, 2011).…”