Abstract
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 (TFH) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 524-530 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 22 |
| Issue number | 5 |
| DOIs | |
| State | Published - 1 May 2016 |
Bibliographical note
Funding Information:This work was supported by US National Institutes of Health (NIH) grant R01 DK61707 (G.N.), the University of Michigan's Cancer Center Support grant 5 P30 CA46592 (G.N.), the DFG Cluster of Excellence 'Inflammation at Interfaces' (P.R.) and the BMBF grant TP5 (P.R.). We thank M. Zeng for critical review of the manuscript, L. Haynes for animal husbandry and the University of Michigan Germ-Free Animal Core Facility and Host Microbiome Initiative (G.N.) for support.
Publisher Copyright:
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