Escherichia coli heat-labile enterotoxin promotes protective Th17 responses against infection by driving innate IL-1 and IL-23 production.

Abstract

Escherichia coli heat-labile enterotoxin (LT) is a powerful mucosal adjuvant; however, it is associated with toxic effects when delivered intranasally, and its mechanism of action is poorly understood. In this article, we demonstrate that LT acts as a highly effective adjuvant when administered parenterally, promoting Ag-specific IL-17, as well as IFN-γ, IL-4, and IL-10 production in response to coadministered Ags. We found that the adjuvant activity of LT was mediated in part by inducing dendritic cell (DC) activation; LT promoted CD80 and CD86 expression by DCs and enhanced IL-1α, IL-1β, and IL-23 production. An LT mutant, LTK63, that lacks enzyme activity was less effective than the wild-type toxin in promoting DC maturation and the development of Ag-specific Th17 cells. LT enhanced IL-23 and IL-1α production from DCs via activation of ERK MAPK and IL-1β secretion through activation of caspase-1 and the NLRP3 inflammasome. These cytokines played a major role in promoting Th17 responses by LT and LTK63. The induction of Th17 cells in vivo in response to LT and LTK63 as adjuvants was significantly reduced in IL-1RI-deficient mice. Finally, using a murine respiratory infection model, we demonstrated that LT can act as a highly effective adjuvant for a pertussis vaccine, promoting Ag-specific Th17 cells and protection against Bordetella pertussis challenge, which was significantly reduced in IL-17-defective mice. Our findings provide clear evidence that LT can promote protective immune responses in part through induction of innate IL-1 and, consequently, Th17 cells.

• Authors: Corinna F Brereton, Caroline E Sutton, Pádraig J Ross, Yoichiro Iwakura, Mariagrazia Pizza, Rino Rappuoli, Ed C Lavelle, Kingston H G Mills
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 10 Pg. 5896-906 (May 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21490151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-1 Antigen
• B7-2 Antigen
• Bacterial Toxins
• Carrier Proteins
• Enterotoxins
• Escherichia coli Proteins
• Interleukin-1
• Interleukin-17
• Interleukin-23
• Interleukin-5
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Interleukin-10
• Interleukin-4
• Interferon-gamma
• heat-labile enterotoxin, E coli
• Extracellular Signal-Regulated MAP Kinases
• Caspase 1

Topics

• Animals
• B7-1 Antigen (genetics)
• B7-2 Antigen (genetics)
• Bacterial Toxins (administration & dosage, immunology, metabolism)
• Bordetella pertussis (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Cell Differentiation (immunology)
• Dendritic Cells (immunology, metabolism)
• Enterotoxins (administration & dosage, immunology, metabolism)
• Escherichia coli (immunology)
• Escherichia coli Proteins (administration & dosage, immunology, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Interferon-gamma (immunology)
• Interleukin-1 (biosynthesis, immunology)
• Interleukin-10 (immunology)
• Interleukin-17 (genetics, immunology)
• Interleukin-23 (biosynthesis, immunology)
• Interleukin-4 (immunology)
• Interleukin-5 (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• NLR Family, Pyrin Domain-Containing 3 Protein
• Th17 Cells (immunology)