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

Kim, Dong-Hyun; Kim, Yun Gi; Seo, Sang Uk; Kamada, Nobuhiko; Prescott, David; Philpott, Dana J.; Rosenstiel, Philip; Inohara, Naohiro; Núñez, Gabriel

doi:10.1038/nm.4075

Cited by 101 publications

(100 citation statements)

References 53 publications

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“…CT has been known as a potent mucosal immunogen and adjuvant for several decades; we confirm and extend a recent report linking these CT properties with the intestinal microbiota 14 . With SFB as a known stimulator of endogenous Th17 cells in the intestine, we found that in addition, other commensal bacteria such as those belonging to the altered Schaedler flora, can also participate in the regulation of intestinal Th17 and antibody responses to CT mucosal immunization.…”

Section: Discussionsupporting

confidence: 89%

“…Mucosal delivery of CT induces strong mucosal and systemic humoral immune responses to itself and co-administered protein antigens 12 , but does not cause intestinal inflammation. CT does so by activating Gsα and the nucleotide-binding oligomerization domain containing 2 (Nod2) expressed in CD11c + cells 13,14 . Th17 cells can convert into T follicular helper (Tfh) cells in the PPs, thus enhancing high-affinity intestinal IgA production 15 , suggesting an important role of Th17 cells in the induction of antigen-specific IgA in the gut, which in turn is involved in the protection against microbial antigens at the mucosal surface 16 .…”

Section: Introductionmentioning

confidence: 99%

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Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota

Zhao

Harbour

Kolde

et al. 2017

The Journal of Immunology

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Th17 cells play a role as an inflammation mediator in a variety of autoimmune disorders, including inflammatory bowel disease (IBD) and thus are widely considered to be pathogenic. However, Th17 cells are present in the normal intestine and show a homeostatic phenotype, i.e., they participate in the maintenance of intestinal homeostasis rather than inducing inflammation. We observed an enlarged Th17 population in the small intestine of C57BL/6.IgA−/− mice compared to wild-type mice, which was further amplified with cholera toxin (CT) immunization without causing intestinal inflammation. The increased Th17 induction and the correspondingly 10-fold higher CTB-specific serum IgG response in C57BL/6.IgA−/− mice after CT immunization was microbiota dependent and was associated with increased segmented filamentous bacteria (SFB) in the small intestine of C57BL/6.IgA−/− mice. Oral administration of vancomycin greatly dampened both CT immunogenicity and adjuvanticity, and the differential CT responses in IgA−/− and wild-type mice disappeared after intestinal microbiota equalization. Using gnotobiotic mouse models, we found that CT induction of homeostatic intestinal Th17 responses was supported not only by SFB but also by other commensal bacteria. Furthermore, transcriptome analysis using IL-17AhCD2 reporter mice revealed a similar gene expression profile in CT-induced intestinal Th17 cells and endogenous intestinal Th17 cells at homeostasis, with upregulated expression of a panel of immune regulatory genes, which was distinctly different from the gene expression profile of pathogenic Th17 cells. Taken together, we identified a non-pathogenic signature of intestinal homeostatic Th17 cells, which are actively regulated by the commensal microbiota and can be selectively stimulated by CT.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota

Zhao

Harbour

Kolde

et al. 2017

The Journal of Immunology

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“…However, higher titers of serum IgG against fecal symbiotic bacteria were frequently reported in patients with either Crohn’s disease or Colitis, which was thought to reflect either prior infections or systemic translocation of gut bacteria in these patients due to “leaky” epithelial barrier (126). In addition, we recently reported that gut symbiotic bacteria promote the adjuvant activity of cholera toxin, an enterotoxin secreted by Vibrio cholera that has been used as a potent mucosal adjuvant, through Nod2-mediated recognition of its microbial agonist by dendritic cells (127). …”

Section: Regulation Of B Cell Immune Response By the Gut Microbiotamentioning

confidence: 99%

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

Pickard

Zeng

Caruso

et al. 2017

Immunological Reviews

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1,183

823

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Summary The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous microorganisms have co-evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease.

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“…2/2 mice were obtained from Dr. J.-P. Hugot (Hôpital Robert Debré, Université Paris Diderot, Paris, France) (14), Villin-Cre (B6.Cg-Tg(Vil-cre) 997Gum/J) and LyzM-Cre (B6.129P2-Lyz2 tm1(cre)Ifo /J) mice were purchased from The Jackson Laboratory (Bar Harbor, ME), and NOD2 flox/flox mice were obtained from Dr. P. Rosenstiel (Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany) (15). NOD2 flox/flox mice were generated by genOway (Lyon, France).…”

Section: Nod2mentioning

confidence: 99%

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Zanello

Goethel

Rouquier

et al. 2016

The Journal of Immunology

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Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn’s disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2−/− mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2−/− mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.

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

Cited by 101 publications

References 53 publications

Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota

Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota

Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

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