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

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

Research output: Contribution to journalArticle

23 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
Externally publishedYes

Fingerprint

Oligomerization
Cholera Toxin
Microbiota
Nucleotides
Bacteria
Immunoglobulin G
Cytokines
Immunization
Antigens
Mucosal Immunity
Helper-Inducer T-Lymphocytes
Plasma Cells
Staphylococcus
Integrins
Cyclic AMP
Dendritic Cells
Vaccination
Thermodynamic properties
Anti-Bacterial Agents
Plasmas

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. / Kim, Donghyun; Kim, Yungi; Seo, Sang Uk; Kim, Dong Jae; Kamada, Nobuhiko; Prescott, Dave; Philpott, Dana J.; Rosenstiel, Philip; Inohara, Naohiro; Núñez, Gabriel.

In: Nature Medicine, Vol. 22, No. 5, 01.05.2016, p. 524-530.

Research output: Contribution to journalArticle

Kim, D, Kim, Y, Seo, SU, Kim, DJ, Kamada, N, Prescott, D, Philpott, DJ, Rosenstiel, P, Inohara, N & Núñez, G 2016, 'Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin', Nature Medicine, vol. 22, no. 5, pp. 524-530. https://doi.org/10.1038/nm.4075
Kim, Donghyun ; Kim, Yungi ; Seo, Sang Uk ; Kim, Dong Jae ; Kamada, Nobuhiko ; Prescott, Dave ; Philpott, Dana J. ; Rosenstiel, Philip ; Inohara, Naohiro ; Núñez, Gabriel. / Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. In: Nature Medicine. 2016 ; Vol. 22, No. 5. pp. 524-530.
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