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Inducible Foxp3^+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Round, June L. and Mazmanian, Sarkis K. (2010) Inducible Foxp3^+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proceedings of the National Academy of Sciences of the United States of America, 107 (27). pp. 12204-12209. ISSN 0027-8424. PMCID PMC2901479. https://resolver.caltech.edu/CaltechAUTHORS:20100803-151102997

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Abstract

To maintain intestinal health, the immune system must faithfully respond to antigens from pathogenic microbes while limiting reactions to self-molecules. The gastrointestinal tract represents a unique challenge to the immune system, as it is permanently colonized by a diverse amalgam of bacterial phylotypes producing multitudes of foreign microbial products. Evidence from human and animal studies indicates that inflammatory bowel disease results from uncontrolled inflammation to the intestinal microbiota. However, molecular mechanisms that actively promote mucosal tolerance to the microbiota remain unknown. We report herein that a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3^+ regulatory T cells (Tregs) with a unique “inducible” genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3^+ T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4^+ T cells into Foxp3^+ Treg cells that produce IL-10 during commensal colonization. Functional Foxp3^+ Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression. Most significantly, we show that PSA is not only able to prevent, but also cure experimental colitis in animals. Our results therefore demonstrate that B. fragilis co-opts the Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0909122107 DOIArticle
http://www.pnas.org/content/107/27/12204.abstractPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901479/PubMed CentralArticle
ORCID:
AuthorORCID
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2010 by the National Academy of Sciences. Freely available online through the PNAS open access option. Edited by Richard A. Flavell, Yale University School of Medicine, Howard Hughes Medical Institute, New Haven, CT, and approved June 2, 2010 (received for review August 13, 2009). We thank members of the Mazmanian laboratory for their critical review of the manuscript and Dr. Talal Chatila (University of California Los Angeles) for the kind gift of the Foxp3-GFP mice, Rochelle A. Diamond for help with cell sorting, and Dr. Gregory W. Lawson (University of California Los Angeles) for providing expert pathology analysis. J.L.R. is a Merck Fellow of the Jane Coffin Child’s Memorial Fund. S.K.M. is a Searle Scholar. Work in the laboratory of the authors is supported by funding from the National Institutes of Health (DK 078938), the Damon Runyon Cancer Research Foundation, and the Crohn’s and Colitis Foundation of America (to S.K.M.). Author contributions: J.L.R. and S.K.M. designed research; J.L.R. performed research; J.L.R. and S.K.M. analyzed data; and J.L.R. and S.K.M. wrote the paper.
Funders:
Funding AgencyGrant Number
Merck Fellow of the Jane Coffin Child's Memorial FundUNSPECIFIED
NIHDK 078938
Damon Runyon Cancer Research FoundationUNSPECIFIED
Crohn's and Colitis Foundation of AmericaUNSPECIFIED
Searle ScholarUNSPECIFIED
Subject Keywords:Bacteroides fragilis; inflammatory bowel disease; Toll-like receptor; polysaccharide A; interleukin 10
Issue or Number:27
PubMed Central ID:PMC2901479
Record Number:CaltechAUTHORS:20100803-151102997
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100803-151102997
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:19265
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Aug 2010 22:34
Last Modified:03 Oct 2019 01:54

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