Journal
NATURE MEDICINE
Volume 22, Issue 5, Pages 524-530Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4075
Keywords
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Funding
- US National Institutes of Health (NIH) [R01 DK61707]
- University of Michigan's Cancer Center [5 P30 CA46592]
- DFG Cluster of Excellence 'Inflammation at Interfaces'
- BMBF [TP5]
- University of Michigan Germ-Free Animal Core Facility
- Host Microbiome Initiative
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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 ltgax) 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.
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