TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells

Abstract

Whole cell pertussis vaccines (Pw) induce Th1 responses and protect against Bordetella pertussis infection, whereas pertussis acellular vaccines (Pa) induce Ab and Th2-biased responses and also protect against severe disease. In this study, we show that Pw failed to generate protective immunity in TLR4-defective C3H/HeJ mice. In contrast, protection induced with Pa was compromised, but not completely abrogated, in C3H/HeJ mice. Immunization with Pw, but not Pa, induced a population of IL-17-producing T cells (Th-17), as well as Th1 cells. Ag-specific IL-17 and IFN-γ production was significantly lower in Pw-immunized TLR4-defective mice. Furthermore, treatment with neutralizing anti-IL-17 Ab immediately before and after B. pertussis challenge significantly reduced the protective efficacy of Pw. Stimulation of dendritic cells (DC) with Pw promoted IL-23, IL-12, IL-1β, and TNF-α production, which was impaired in DC from TLR4-defective mice. B. pertussis LPS, which is present in high concentrations in Pw, induced IL-23 production by DC, which enhanced IL-17 secretion by T cells, but the induction of Th-17 cells was also dependent on IL-1. In addition, we identified a new effector function for IL-17, activating macrophage killing of B. pertussis, and this bactericidal activity was less efficient in macrophages from TLR4-defective mice. These data provide the first definitive evidence of a role for TLRs in protective immunity induced by a human vaccine. Our findings also demonstrate that activation of innate immune cells through TLR4 helps to direct the induction of Th1 and Th-17 cells, which mediate protective cellular immunity to B. pertussis.

Induction, function and regulation of IL‐17‐producing T cells

“…Experimental autoimmune disease in many animal models such as EAE, EAU and CIA is induced by immunization with autoantigen in the presence of CFA; this is likely to involve the activation of innate inflammatory cytokines that drive Th1 and Th17 cells. Indeed there is already evidence that pathogens or PAMPs can promote the production of inflammatory cytokines from monocytes and DC, which activate IL-17 production by T cells [14,38,64]. Stimulation of DC with TLR3, TLR4 and TLR9 ligands was found to induce MyD88-dependent production of cytokines that promoted differentiation of IL-17 producing CD4 1 T cells [41].…”

“…These studies established a pathogenic role for Th17 cells in organ-specific autoimmune and chronic inflammatory diseases. Th17 cells have also been shown to play a protective role in immunity to infection, where they help to promote pathogen clearance by enhancing neutrophil recruitment to sites of infection and activating macrophages [13,14].…”

“…Stimulation of DC with TLR3, TLR4 and TLR9 ligands was found to induce MyD88-dependent production of cytokines that promoted differentiation of IL-17 producing CD4 1 T cells [41]. We have reported that the Gram-negative bacteria Bordetella pertussis or LPS purified from this bacteria induce TLR4-dependent IL-1 and IL-23 production from DC, which in turn leads to the induction of IL-17 production by murine antigen-specific memory T cells [14]. Similarly, bacterial-derived ligands for the intracellular PRRs, NOD-2, such as MDP, have also been shown to drive IL-17 production by human memory T cells by stimulating IL-1 and IL-23 production by DC [38].…”

“…These studies established a pathogenic role for Th17 cells in organ-specific autoimmune and chronic inflammatory diseases. Th17 cells have also been shown to play a protective role in immunity to infection, where they help to promote pathogen clearance by enhancing neutrophil recruitment to sites of infection and activating macrophages [13,14].This review addresses the contribution of different T-cell subtypes to IL-17 production, the role of innate cytokines in promoting the differentiation and expansion of IL-17-producing T cells, the stimuli and signalling pathways for induction of these innate cytokines, the regulation of IL-17 production and the function of IL-17 in the pathogenesis of autoimmunity and in protection against infection. …”

“…Here vaccination with M. tuberculosis antigens in adjuvants induces IL-17-producing CD4 1 T cells, which after bacterial challenge promote chemokine production and recruit protective Th1 cells [89]. IL-17-producing T cells, activated by innate IL-1 and IL-23 production, also function with Th1 cells to mediate natural and vaccine-induced immunity to B. pertussis [14,91].Studies on the role of IL-17-producing T cells in immunity to fungal infections have generated more conflicting findings. Clearance of the fungal pathogen Crypotococcus neoformans is delayed and survival reduced in IL-23p19 À/À mice [92].…”