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Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin
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Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin
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Journal Article
Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin
2016
Overview
The mucosal adjuvant activity of cholera toxin depends on the microbiota, which signals through Nod2 on CD11c
+
cells.
Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (T
FH
) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by
Itgax
) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with
Staphylococcus sciuri
, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/31
/ 631/250
/ Acetylmuramyl-Alanyl-Isoglutamine - pharmacology
/ Adjuvants, Immunologic - pharmacology
/ Animals
/ Anti-Bacterial Agents - pharmacology
/ Cellular signal transduction
/ Cholera
/ Cholera Toxin - pharmacology
/ Dendritic Cells - immunology
/ Enzyme-Linked Immunospot Assay
/ Immunity, Mucosal - drug effects
/ Immunity, Mucosal - immunology
/ Mice
/ Microbiota (Symbiotic organisms)
/ Mucous Membrane - immunology
/ Nod2 Signaling Adaptor Protein - agonists
/ Nod2 Signaling Adaptor Protein - drug effects
/ Nod2 Signaling Adaptor Protein - immunology
/ Real-Time Polymerase Chain Reaction
/ Staphylococcal Infections - immunology
/ Testing
/ Toxins
/ Vaccines
