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

Authors:
Donghyun Kim, Yun-Gi Kim, Sang-Uk Seo, Dong-Jae Kim, Nobuhiko Kamada, Dave Prescott, Dana J Philpott, Philip Rosenstiel, Naohiro Inohara, Gabriel Núñez
Year of publication:
2016
Volume:
22
Issue:
5
Issn:
1078-8956
Journal title abbreviated:
NAT MED
Journal title long:
Nature medicine
Impact factor:
30.357
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.