Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis.
Item Type:Journal Article
Citation:Dunne A, Ross PJ, Pospisilova E, Masin J, Meaney A, Sutton CE, Iwakura Y, Tschopp J, Sebo P, Mills KH, Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis., Journal of Immunology, 185, 3, 2010, 1711-9
Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis.pdf (Published (publisher's copy) - Peer Reviewed) 879.7Kb
Inflammasome-mediated IL-1? production is central to the innate immune defects that give rise to certain autoinflammatory diseases and may also be associated with the generation of IL-17?producing CD4+ T (Th17) cells that mediate autoimmunity. However, the role of the inflammasome in driving adaptive immunity to infection has not been addressed. In this article, we demonstrate that inflammasome-mediated IL-1? plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection. Using a murine respiratory challenge model, we demonstrated that the course of B. pertussis infection was significantly exacerbated in IL-1R type I-defective (IL-1RI?/?) mice. We found that adenylate cyclase toxin (CyaA), a key virulence factor secreted by B. pertussis, induced robust IL-1? production by dendritic cells through activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins, we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclase enzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promoted the induction of Ag-specific Th17 cells in wild-type but not IL-1RI?/? mice. Furthermore, the bacterial load was enhanced in IL-17?defective mice. Our findings demonstrate that CyaA, a virulence factor from B. pertussis, promotes innate IL-1? production via activation of the NALP3 inflammasome and, thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subverting host immunity, our findings suggest that CyaA can promote IL-1??mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.
Type of material:Journal Article
Series/Report no:Journal of Immunology
Availability:Full text available
Subject (TCD):Immunology, Inflammation & Infection