title: 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.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Corinna F
authors.initials: CF
authors.lastname: Brereton
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sutton
authors.forename: Pádraig J
authors.initials: PJ
authors.lastname: Ross
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics; D051940:B7-2 Antigen / Q000235:genetics; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D001886:Bordetella pertussis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001427:Bacterial Toxins; D002352:Carrier Proteins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D015848:Interleukin-5; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; C027538:heat-labile enterotoxin, E coli; D048049:Extracellular Signal-Regulated MAP Kinases; D020170:Caspase 1