Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin

Donghyun Kim, Yun Gi Kim, Sang Uk Seo, Dong Jae Kim, Nobuhiko Kamada, Dave Prescott, Dana J. Philpott, Philip Rosenstiel, Naohiro Inohara, Gabriel Núñez

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35 Citations (Scopus)

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 languageEnglish
Pages (from-to)524-530
Number of pages7
JournalNature medicine
Volume22
Issue number5
DOIs
Publication statusPublished - 2016 May 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kim, D., Kim, Y. G., Seo, S. U., Kim, D. J., Kamada, N., Prescott, D., Philpott, D. J., Rosenstiel, P., Inohara, N., & Núñez, G. (2016). Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. Nature medicine, 22(5), 524-530. https://doi.org/10.1038/nm.4075