Back to Search
Start Over
Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 Aug 01; Vol. 185 (3), pp. 1711-9. Date of Electronic Publication: 2010 Jul 07. - Publication Year :
- 2010
-
Abstract
- Inflammasome-mediated IL-1beta 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-1beta 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-1beta 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-1beta 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-1beta-mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.
- Subjects :
- Adenylate Cyclase Toxin toxicity
Animals
CD4-Positive T-Lymphocytes enzymology
CD4-Positive T-Lymphocytes microbiology
Carrier Proteins metabolism
Caspase 1 metabolism
Cell Polarity immunology
Cells, Cultured
Epitopes, T-Lymphocyte immunology
Inflammation enzymology
Inflammation microbiology
Inflammation prevention & control
Inflammation Mediators physiology
Interleukin-17 deficiency
Interleukin-17 physiology
Interleukin-1beta biosynthesis
Interleukin-1beta physiology
Intubation, Intratracheal
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein
Respiratory Tract Infections enzymology
Respiratory Tract Infections microbiology
Respiratory Tract Infections pathology
Adenylate Cyclase Toxin physiology
Bordetella pertussis immunology
CD4-Positive T-Lymphocytes immunology
Inflammation Mediators metabolism
Interleukin-17 biosynthesis
Respiratory Tract Infections prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 185
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 20610650
- Full Text :
- https://doi.org/10.4049/jimmunol.1000105