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Cholera toxin, and the related nontoxic adjuvants mmCT and dmLT, promote human Th17 responses via cyclic AMP-protein kinase A and inflammasome-dependent IL-1 signaling

Journal article
Authors Maximilian Larena
Jan Holmgren
Michael Lebens
Manuela Terrinoni
Anna Lundgren
Published in Journal of Immunology
Volume 194
Issue 8
Pages 3829-39
ISSN 0022-1767
Publication year 2015
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 3829-39
Language en
Keywords Adaptor Proteins, Signal Transducing/immunology, Adjuvants, Immunologic/ pharmacology, Adult, Apoptosis Regulatory Proteins/immunology, CARD Signaling Adaptor Proteins/immunology, Calcium-Binding Proteins/immunology, Carrier Proteins/immunology, Caspase 1/immunology, Cholera Toxin/ pharmacology, Cyclic AMP/ immunology, Cyclic AMP-Dependent Protein Kinases/ immunology, Enzyme Activation/drug effects/immunology, Female, Humans, Inflammasomes/ immunology, Interleukin-1beta/ immunology, Male, Middle Aged, Signal Transduction/ drug effects/immunology, Th17 Cells/cytology/ immunology
Subject categories Immunology in the medical area


We have examined the molecular pathways involved in the adjuvant action of cholera toxin (CT) and two novel nontoxic molecules, multiple-mutated CT (mmCT) and double-mutant heat-labile toxin (dmLT) on human T cell responses. Human PBMCs or isolated monocytes were stimulated in vitro with CT, mmCT, or dmLT plus a polyclonal stimulus (staphylococcal enterotoxin B) or specific bacterial Ags, and effects on expression of cytokines and signaling molecules were determined. CT, mmCT, and dmLT strongly enhanced IL-17A and to a lesser extent IL-13 responses, but had little effect on IFN-gamma production or cell proliferation. Intracellular cytokine staining revealed that the enhanced IL-17A production was largely confined to CD4(+) T cells and coculture experiments showed that the IL-17A promotion was effectively induced by adjuvant-treated monocytes. Relative to CT, mmCT and dmLT induced at least 100-fold lower levels of cAMP, yet this cAMP was enough and essential for the promotion of Th17 responses. Thus, inhibition of cAMP-dependent protein kinase A was abolished, and stimulation with a cAMP analog mimicked the adjuvant effect. Furthermore, CT, mmCT, and dmLT induced IL-1beta production and caspase-1 activation in monocytes, which was associated with increased expression of key proinflammatory and inflammasome-related genes, including NLRP1, NLRP3, and NLRC4. Inflammasome inhibition with a specific caspase-1 inhibitor, or blocking of IL-1 signaling by IL-1 receptor antagonist, abrogated the Th17-promoting effect. We conclude that CT, mmCT, and dmLT promote human Th17 responses via cAMP-dependent protein kinase A and caspase-1/inflammasome-dependent IL-1 signaling.

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