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

Zhao, Q; Harbour, SN; Kolde, R; Latorre, IJ; Tun, HM; Schoeb, TR; Turner, H; ... Elson, CO; + view all (2017) Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota. Journal of Immunology , 199 (1) pp. 312-322. 10.4049/jimmunol.1700171.

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Abstract

Th17 cells play a role as an inflammation mediator in a variety of autoimmune disorders, including inflammatory bowel disease, and thus are widely considered to be pathogenic. However, Th17 cells are present in the normal intestine and show a homeostatic phenotype; that is, 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 with 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 CT B subunit-specific serum IgG response in IgA-/- mice after CT immunization was microbiota dependent and was associated with increased segmented filamentous bacteria in the small intestine of 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 segmented filamentous bacteria, 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 nonpathogenic signature of intestinal homeostatic Th17 cells, which are actively regulated by the commensal microbiota and can be selectively stimulated by CT.

Type: Article
Title: Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota
Location: United States
DOI: 10.4049/jimmunol.1700171
Publisher version: https://doi.org/10.4049/jimmunol.1700171
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Animals, Cholera Toxin, Gastrointestinal Microbiome, Gene Expression Profiling, Germ-Free Life, Homeostasis, IgA Deficiency, Immunoglobulin A, Inflammatory Bowel Diseases, Intestinal Mucosa, Intestine, Small, Mice, Mice, Inbred C57BL, Th17 Cells, Vancomycin
URI: http://discovery.ucl.ac.uk/id/eprint/10052188
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